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Peripheral Mechanisms of Itch

  • Changxiong J. Guo
    Affiliations
    Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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  • Nathaniel S. Grabinski
    Affiliations
    Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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  • Qin Liu
    Correspondence
    Correspondence: Qin Liu, Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, 660 South Euclid Avenue, CB8054, St. Louis, Missouri 63110, USA.
    Affiliations
    Center for the Study of Itch & Sensory Disorders, Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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Published:November 24, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.024
      Itch is a universally experienced sensation, and chronic itch can be as diabolically debilitating as pain. Recent advances have not only identified the neuronal itch sensing circuitry, but also have uncovered the intricate interactions between skin and immune cells that work together with neurons to identify itch-inducing irritants. In this review, we will summarize the fundamental mechanisms of acute itch detection in the skin, as well as highlight the recent discoveries relating to this topic.

      Abbreviations:

      5-HT (5-hydroxytryptamine), ACD (allergic contact dermatitis), AD (atopic dermatitis), AEW (acetone:ether water), CGRP (calcitonin gene-related peptide), CTCL (cutaneous T-cell lymphoma), DRG (dorsal root ganglia), GRP (gastrin-releasing peptide), HTR (serotonin receptor), KC (keratinocyte), KOR (κ-opioid receptor), LTC4 (cysteinyl leukotriene), LTMR (low-threshold mechanoreceptor), miR (microRNA), NP (nonpeptidergic), NPPB (brain natriuretic peptide), PAR (protease-activated receptor), SP (substance P), Th (T helper), TG (trigeminal ganglia), TLR (toll-like receptor)

      Introduction

      Itch, also known as pruritus, is generally defined as an unpleasant sensation that evokes an instinctive urge to scratch. Similar to pain, itch evolved as a protective mechanism against harmful external elements. Whereas pain triggers immediate withdrawal from hazard, itch-induced scratching removes irritants from the skin. Despite the distinctiveness of itch sensation and its associated behavioral reflexes, itch was not fully appreciated as a separate sensory process until relatively recently. Itch and pain-sensing neural circuits were once theorized to be overlapping. Itch had been thought to be simply a low-intensity activation of pain-sensing circuits, largely due to the broad expression of noxious chemical receptors in itch-sensing neurons, such as the capsaicin receptor TRPV1 or the mustard oil receptor TRPA1 (
      • Ward L.
      • Wright E.
      • McMahon S.B.
      A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain.
      ). Nevertheless, starting with the discovery of itch selective MRGPRs in primary afferents of the peripheral nervous system (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ;
      • Liu Q.
      • Sikand P.
      • Ma C.
      • Tang Z.
      • Han L.
      • Li Z.
      • et al.
      Mechanisms of itch evoked by β-alanine.
      ,
      • Liu Q.
      • Weng H.J.
      • Patel K.N.
      • Tang Z.
      • Bai H.
      • Steinhoff M.
      • et al.
      The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
      ,
      • Liu Q.
      • Tang Z.
      • Surdenikova L.
      • Kim S.
      • Patel K.N.
      • Kim A.
      • et al.
      Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
      ) and gastrin-releasing peptide (GRP) signaling circuits in the CNS (
      • Sun Y.G.
      • Chen Z.F.
      A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
      ), itch is now recognized as a distinct biological process.
      Research progress has also transformed itch research into a multidisciplinary field of study. Despite its conceptual simplicity, itch detection is an extraordinary task. The skin is continually assaulted by a barrage of diverse environmental irritants—ranging from UV, chemicals, and allergens to a host of bioactive compounds, peptides, and proteases from bugs, microbes, and pathogens—that all must be promptly detected and deciphered. Although itch-sensing neurons possess a repertoire of receptors that allows for a degree of direct exogenous irritants detection, itch is often initiated by epidermal and immune cells, and passed to sensory afferents through endogenous itch mediators. Findings over the past decade have clearly shown that itch detection is not purely a neuronal phenomenon but rather a complex orchestra of skin, immune, and neural processes that work in concert to complete this enormous task (
      • Wang F.
      • Kim B.S.
      Itch: a paradigm of neuroimmune crosstalk.
      ).
      In this review, we will summarize the recent advances of this field and our current understanding of the main mechanisms of itch detection. We will first briefly summarize the neuronal receptors and primary afferent populations that mediate itch sensation. Then, we will discuss the cellular and molecular mechanisms of itch detection in the skin (Figure 1).
      Figure thumbnail gr1
      Figure 1Schematic of acute itch detection in the mouse skin. Allergens and pruritogens induce itch through three main mechanisms: (i) certain external pruritogens, such as chloroquine or proteases, activate itch-sensing primary afferent neurons directly through their MRGPR receptors. (ii) Allergens and other pruritogenic compounds activate mast cells through their IgE-bound FcεR1 and MRGPRB2 receptors, respectively. Activated mast cells activate itch-sensing neurons in turn through the release of histamine, serotonin, proteases, and MRGPR agonists. (iii) Pruritogenic compounds may also, directly or indirectly, activate keratinocytes or induce cutaneous inflammation. Activated keratinocytes induce itch through the release of neuronal agonists or through mast cell activation. 5-HT, 5-hydroxytryptamine; HTR, 5-hydroxytryptamine receptor; miR, microRNA; NP, nonpeptidergic; Th, T helper.

      Neuronal and nonneuronal itch receptors

      Although itch biology is an extraordinarily complex process, itch detection and signaling are largely accomplished through only six receptor families. Many of these receptors were first characterized in the skin and immune cells, where they play important roles in irritant detection and immune response. Their functions in these contexts are far too diverse and complex for the purposes of this review. Nevertheless, their involvement in itch initiation or mediation will be briefly discussed in the following section.
      Histaminergic signaling was the earliest described itch process and remains the gold standard of the field (
      • Bickford R.G.
      Experiments relating to the itch sensation, its peripheral mechanism, and central pathways.
      ;
      • Han S.K.
      • Mancino V.
      • Simon M.I.
      Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons.
      ;
      • Inagaki N.
      • Nakamura N.
      • Nagao M.
      • Musoh K.
      • Kawasaki H.
      • Nagai H.
      Participation of histamine H1 and H2 receptors in passive cutaneous anaphylaxis-induced scratching behavior in ICR mice.
      ). There are four known histamine receptors, HRH1‒4, with distributed expression across a variety of tissues (
      • Hill S.J.
      • Ganellin C.R.
      • Timmerman H.
      • Schwartz J.C.
      • Shankley N.P.
      • Young J.M.
      • et al.
      International Union of Pharmacology. XIII. Classification of histamine receptors.
      ). These receptors play enormously important roles in both innate and adaptive immunity, mediating chemotaxis, cellular polarization, and cytokine release in a highly compartmentalized and dose-dependent manner (
      • Dunford P.J.
      • O’Donnell N.
      • Riley J.P.
      • Williams K.N.
      • Karlsson L.
      • Thurmond R.L.
      The histamine H 4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells.
      ;
      • Gutzmer R.
      • Diestel C.
      • Mommert S.
      • Köther B.
      • Stark H.
      • Wittmann M.
      • et al.
      Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells.
      ;
      • Hofstra C.L.
      • Desai P.J.
      • Thurmond R.L.
      • Fung-Leung W.P.
      Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells.
      ;
      • Jutel M.
      • Watanabe T.
      • Klunker S.
      • Akdis M.
      • Thomet O.A.
      • Malolepszy J.
      • et al.
      Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors.
      ;
      • Strakhova M.I.
      • Nikkel A.L.
      • Manelli A.M.
      • Hsieh G.C.
      • Esbenshade T.A.
      • Brioni J.D.
      • et al.
      Localization of histamine H4 receptors in the central nervous system of human and rat.
      ). In the context of itch, histamine is liberally released by mast cells upon degranulation and produces itch sensation directly through neuronal HRH activation (
      • Dimitriadou V.
      • Rouleau A.
      • Dam Trung Tuong M.
      • Newlands G.J.F.
      • Miller H.R.P.
      • Luffau G.
      • et al.
      Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen.
      ;
      • Rossbach K.
      • Nassenstein C.
      • Gschwandtner M.
      • Schnell D.
      • Sander K.
      • Seifert R.
      • et al.
      Histamine H1, H 3 and H 4 receptors are involved in pruritus.
      ;
      • Shim W.S.
      • Tak M.H.
      • Lee M.H.
      • Kim M.
      • Kim M.
      • Koo J.Y.
      • et al.
      TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase.
      ). In mice, HRH1 and HRH4 are expressed by dorsal root ganglia (DRG) neurons, where their expression is localized to two populations of itch-sensing nonpeptidergic (NP) nociceptors (
      • Chiu I.M.
      • Barrett L.B.
      • Williams E.K.
      • Strochlic D.E.
      • Lee S.
      • Weyer A.D.
      • et al.
      Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity [published correction appears in Elife 2015;4:e06720].
      ;
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ;
      • Zeisel A.
      • Hochgerner H.
      • Lönnerberg P.
      • Johnsson A.
      • Memic F.
      • van der Zwan J.
      • et al.
      Molecular architecture of the mouse nervous system.
      ). In humans, histaminergic itch signaling is largely similar, although only HRH1 has been conclusively shown to be expressed by primary sensory afferents (
      • Timmerman H.
      • Leurs R.
      • Van Der Goot H.
      Histamine receptors and their ligands: mechanisms and applications.
      ).
      The MRGPR family of receptors was discovered and characterized relatively recently, but has quickly become a quintessential family of neuronal itch sensors (
      • Dong X.
      • Han S.
      • Zylka M.J.
      • Simon M.I.
      • Anderson D.J.
      A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.
      ;
      • Liu Q.
      • Sikand P.
      • Ma C.
      • Tang Z.
      • Han L.
      • Li Z.
      • et al.
      Mechanisms of itch evoked by β-alanine.
      ,
      • Liu Q.
      • Weng H.J.
      • Patel K.N.
      • Tang Z.
      • Bai H.
      • Steinhoff M.
      • et al.
      The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
      ). These receptors are broadly required for the detection of both exogenous pruritogens, as well as endogenous itch mediators from keratinocytes (KCs) and immune cells—especially in histamine-independent itch processes. In mice, MRGPRs comprise a family of ∼50 receptors, half of which are pseudogenes. Many MRGPRs show highly restricted expression to NP nociceptors (
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ). Genetic deletion of a cluster of 12 MRGPR receptors in mice produced overarching itch defects, including insensitivity to many acute pruritogens as well as significantly attenuated itch in chronic models (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ;
      • Huang C.C.
      • Kim Y.S.
      • Olson W.P.
      • Li F.
      • Guo C.
      • Luo W.
      • et al.
      A histamine-independent itch pathway is required for allergic ocular itch.
      ;
      • Liu Q.
      • Sikand P.
      • Ma C.
      • Tang Z.
      • Han L.
      • Li Z.
      • et al.
      Mechanisms of itch evoked by β-alanine.
      ,
      • Liu Q.
      • Weng H.J.
      • Patel K.N.
      • Tang Z.
      • Bai H.
      • Steinhoff M.
      • et al.
      The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
      ,
      • Liu Q.
      • Tang Z.
      • Surdenikova L.
      • Kim S.
      • Patel K.N.
      • Kim A.
      • et al.
      Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
      ;
      • Meixiong J.
      • Vasavda C.
      • Green D.
      • Zheng Q.
      • Qi L.
      • Kwatra S.G.
      • et al.
      Identification of a bilirubin receptor that may mediate a component of cholestatic itch.
      ). In humans, this family is condensed into just eight known members. Nevertheless, the functional scope of human MRGPRs is remarkably well-conserved, with some receptors showing condensed functions of two or more murine counterparts (
      • Dong X.
      • Dong X.
      Peripheral and central mechanisms of itch.
      ).
      Serotoninergic (5-hydroxytryptamine [5-HT]) signaling comprises the third major neuronal itch pathway. In the skin, serotonin receptors (HTRs) are expressed by both immune cells and sensory neurons, and modulate both immune response and sensory perception in a highly complex, context-dependent manner (
      • Mössner R.
      • Lesch K.P.
      Role of serotonin in the immune system and in neuroimmune interactions.
      ). In the context of itch, HTRs are expressed by both murine and human DRG neurons (
      • Flegel C.
      • Schöbel N.
      • Altmüller J.
      • Becker C.
      • Tannapfel A.
      • Hatt H.
      • et al.
      RNA-seq analysis of human trigeminal and dorsal root ganglia with a focus on chemoreceptors.
      ;
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ), and serotonin application is acutely pruritogenic in both species (
      • Morita T.
      • McClain S.P.
      • Batia L.M.
      • Pellegrino M.
      • Wilson S.R.
      • Kienzler M.A.
      • et al.
      HTR7 mediates serotonergic acute and chronic itch.
      ;
      • Weisshaar E.
      • Dunker N.
      • Röhl F.W.
      • Gollnick H.
      Antipruritic effects of two different 5-HT3 receptor antagonists and an antihistamine in haemodialysis patients.
      ). In mice specifically, 5-HT is released by mast cells and acts as a pruritogen at lower doses than histamine (
      • Morita T.
      • McClain S.P.
      • Batia L.M.
      • Pellegrino M.
      • Wilson S.R.
      • Kienzler M.A.
      • et al.
      HTR7 mediates serotonergic acute and chronic itch.
      ). Genetic deletion of Htr7 in mice has been shown to completely abolish serotonergic itch as well as to attenuate many types of chronic itch (
      • Morita T.
      • McClain S.P.
      • Batia L.M.
      • Pellegrino M.
      • Wilson S.R.
      • Kienzler M.A.
      • et al.
      HTR7 mediates serotonergic acute and chronic itch.
      ).
      Toll-like receptors (TLRs) are pattern-recognizing receptors that detect pathogen-associated molecular patterns (
      • Akira S.
      • Uematsu S.
      • Takeuchi O.
      Pathogen recognition and innate immunity.
      ;
      • El-Zayat S.R.
      • Sibaii H.
      • Mannaa F.A.
      Toll-like receptors activation, signaling, and targeting: an overview.
      ). There are 14 known TLRs in mice, with expression across KCs, immune cells, and neurons alike (
      • Diogenes A.
      • Ferraz C.C.
      • Akopian A.N.
      • Henry M.A.
      • Hargreaves K.M.
      LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons.
      ;
      • Duan B.
      • Cheng L.
      • Ma Q.
      Spinal circuits transmitting mechanical pain and itch.
      ;
      • El-Zayat S.R.
      • Sibaii H.
      • Mannaa F.A.
      Toll-like receptors activation, signaling, and targeting: an overview.
      ;
      • Liu T.
      • Berta T.
      • Xu Z.Z.
      • Park C.K.
      • Zhang L.
      • Lü N.
      • et al.
      TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice.
      ,
      • Liu T.
      • Xu Z.Z.
      • Park C.K.
      • Berta T.
      • Ji R.R.
      Toll-like receptor 7 mediates pruritus.
      ;
      • Qi J.
      • Buzas K.
      • Fan H.
      • Cohen J.I.
      • Wang K.
      • Mont E.
      • et al.
      Painful pathways induced by TLR stimulation of dorsal root ganglion neurons.
      ). Four of these receptors, TLR3, TLR4, TLR5, and TLR7, have been reported to mediate itch in mice (
      • Duan B.
      • Cheng L.
      • Ma Q.
      Spinal circuits transmitting mechanical pain and itch.
      ;
      • Liu T.
      • Han Q.
      • Chen G.
      • Huang Y.
      • Zhao L.X.
      • Berta T.
      • et al.
      Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice.
      ,
      • Liu T.
      • Berta T.
      • Xu Z.Z.
      • Park C.K.
      • Zhang L.
      • Lü N.
      • et al.
      TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice.
      ,
      • Liu T.
      • Xu Z.Z.
      • Park C.K.
      • Berta T.
      • Ji R.R.
      Toll-like receptor 7 mediates pruritus.
      ). In addition, TLR3 and TLR7 activation may also lead to prolonged enhancement of itch neuron excitability, likely through a transcriptional mechanism because genetic deletion of these TLRs leads to broad attenuation of acute itch sensitivity (
      • Liu T.
      • Berta T.
      • Xu Z.Z.
      • Park C.K.
      • Zhang L.
      • Lü N.
      • et al.
      TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice.
      ,
      • Liu T.
      • Xu Z.Z.
      • Park C.K.
      • Berta T.
      • Ji R.R.
      Toll-like receptor 7 mediates pruritus.
      ). However, the exact mechanism behind TLR-mediated itch is unclear. Direct neuronal activation has been proposed, but influence from epidermal and immune cell TLR is difficult to isolate in experimental settings.
      Protease-activated receptors (PARs) detect a range of exogenous and endogenous proteases, including mast cell‒derived tryptases, chymases, and cathepsins (
      • Kempkes C.
      • Buddenkotte J.
      • Cevikbas F.
      • Buhl T.
      • Steinhoff M.
      • Carstens E.
      • et al.
      Role of PAR-2 in Neuroimmune Communication and Itch.
      ;
      • Reddy V.B.
      • Iuga A.O.
      • Shimada S.G.
      • LaMotte R.H.
      • Lerner E.A.
      Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors.
      ;
      • Reddy V.B.
      • Lerner E.A.
      Plant cysteine proteases that evoke itch activate protease-activated receptors.
      ). These receptors are expressed by KCs, immune cells, and neurons (
      • Böhm S.K.
      • Khitin L.M.
      • Grady E.F.
      • Aponte G.
      • Payan D.G.
      • Bunnett N.W.
      Mechanisms of desensitization and resensitization of proteinase-activated receptor-2.
      ), and of the four known receptors, PAR2 and PAR4 have been implicated in itch initiation (
      • Akiyama T.
      • Merrill A.W.
      • Zanotto K.
      • Carstens M.I.
      • Carstens E.
      Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice.
      ;
      • Steinhoff M.
      • Neisius U.
      • Ikoma A.
      • Fartasch M.
      • Heyer G.
      • Skov P.S.
      • et al.
      Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.
      ). PAR activation is a two-step process involving proteolytic cleavage of its N-terminal tethered ligand, followed by autoactivation by the released ligand. In the case of PAR2, the tethered ligand SLIGRL-NH2 or SLIGKV-NH2 from mouse and human PAR2, respectively, is also a potent agonist of murine MRGPRC11 and human MRGPRX2 receptors (
      • Akiyama T.
      • Lerner E.A.
      • Carstens E.
      Protease-activated receptors and itch.
      ;
      • Liu Q.
      • Weng H.J.
      • Patel K.N.
      • Tang Z.
      • Bai H.
      • Steinhoff M.
      • et al.
      The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
      ). However, the mechanism of PAR-induced itch is somewhat contentious. In mice, deletion of the MRGPR cluster leads to complete abolishment of PAR2 ligand‒induced itch, whereas deletion of PAR2 receptors did not result in appreciable attenuation of itch response (
      • Liu Q.
      • Weng H.J.
      • Patel K.N.
      • Tang Z.
      • Bai H.
      • Steinhoff M.
      • et al.
      The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
      ;
      • Reddy V.B.
      • Sun S.
      • Azimi E.
      • Elmariah S.B.
      • Dong X.
      • Lerner E.A.
      Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs.
      ). Moreover, activation of PAR2 using a truncated, PAR2-specific peptide ligand was found to elicit pain instead of itch (
      • Liu Q.
      • Weng H.J.
      • Patel K.N.
      • Tang Z.
      • Bai H.
      • Steinhoff M.
      • et al.
      The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
      ), strongly suggesting that PAR2 ligands induce itch indirectly through MRGPRS.
      Finally, cytokines related to type 2 immune response and their receptors are becoming increasingly recognized for their role in itch modulation. TSLP is a major instigator of T helper (Th) 2 response (
      • Kim B.S.
      • Siracusa M.C.
      • Saenz S.A.
      • Noti M.
      • Monticelli L.A.
      • Sonnenberg G.F.
      • et al.
      TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
      ), and its receptor complex, IL7Rα/TSLPR, was reported to be expressed by a small subset of itch-sensing DRG neurons (
      • Wilson S.R.
      • Thé L.
      • Batia L.M.
      • Beattie K.
      • Katibah G.E.
      • McClain S.P.
      • et al.
      The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
      ). High TSLP skin expression is a hallmark feature of atopic dermatitis (AD) (
      • Jariwala S.P.
      • Abrams E.
      • Benson A.
      • Fodeman J.
      • Zheng T.
      The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis.
      ), and TSLP is released by KCs in response to a broad range of stimuli, including in allergy and proteolytic PAR2 activation (
      • Kouzaki H.
      • O’Grady S.M.
      • Lawrence C.B.
      • Kita H.
      Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2.
      ;
      • Moniaga C.S.
      • Jeong S.K.
      • Egawa G.
      • Nakajima S.
      • Hara-Chikuma M.
      • Jeon J.E.
      • et al.
      Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.
      ). In mice, intradermal TSLP injection was reported to induce acute itch, and direct neuronal TSLPR activation has been purported to be a major pruritogenic mechanism (
      • Wilson S.R.
      • Thé L.
      • Batia L.M.
      • Beattie K.
      • Katibah G.E.
      • McClain S.P.
      • et al.
      The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
      ).
      IL-33 is another important KC-derived initiator of Th2 response (
      • Brandt E.
      • Sivaprasad U.
      Th2 cytokines and atopic dermatitis.
      ), and its receptor complex, ST2/IL1RAP, is likewise expressed by a subset of histamine-sensitive DRG neurons. However, the exact involvement of IL-33 in itch is less clear. Although this cytokine is important for the development of chronic itch conditions such as allergic contact dermatitis (ACD) and xerosis, IL-33 is a weak neuronal agonist and does not induce acute itch in naïve mice (
      • Liu B.
      • Tai Y.
      • Achanta S.
      • Kaelberer M.M.
      • Caceres A.I.
      • Shao X.
      • et al.
      IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.
      ). Alternatively, IL-33 has been reported to stimulate enkephalin production in group 2 innate lymphoid cells (
      • Brestoff J.R.
      • Kim B.S.
      • Saenz S.A.
      • Stine R.R.
      • Monticelli L.A.
      • Sonnenberg G.F.
      • et al.
      Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.
      ). The derivative of proenkephalin A—bovine adrenal medulla 8-22–is a potent MRGPR agonist (
      • Dong X.
      • Han S.
      • Zylka M.J.
      • Simon M.I.
      • Anderson D.J.
      A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.
      ). However, a direct functional connection has not yet been demonstrated.
      Finally, type 2 immune cell‒derived ILs–IL-4, IL-13, and IL-31–and their receptors play a major role in AD-associated itch (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ). The involvement of these cytokines in AD skin disease had already been known, but these cytokines have recently also been implicated in the direct modulation of itch neurons. In mice, the IL-4 and IL-13 receptor complex IL-4Rα/IL-13Rα1 is broadly expressed by itch-sensing DRG neurons, and the IL-31 receptor complex IL-31Rα/OSMRβ is further expressed by some 5-HT‒sensitive fractions of these neurons (
      • Chiu I.M.
      • Barrett L.B.
      • Williams E.K.
      • Strochlic D.E.
      • Lee S.
      • Weyer A.D.
      • et al.
      Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity [published correction appears in Elife 2015;4:e06720].
      ;
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ;
      • Zeisel A.
      • Hochgerner H.
      • Lönnerberg P.
      • Johnsson A.
      • Memic F.
      • van der Zwan J.
      • et al.
      Molecular architecture of the mouse nervous system.
      ). The expression of these receptors has also been detected in human DRGs (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ). Intradermal injection of IL-31 produces mild itch in mice, but perhaps more importantly, these cytokines broadly enhance itch neuronal excitability, thereby potentiating both histaminergic and nonhistaminergic itch pathways (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ). Anti–IL-4 therapies have already shown great efficacy in treating moderate to severe cases of AD (
      • Thaçi D.
      • Simpson E.L.
      • Beck L.A.
      • Bieber T.
      • Blauvelt A.
      • Papp K.
      • et al.
      Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.
      ). Now, Jak inhibitors, which target the shared downstream signaling pathways of these IL receptors, are beginning to show promising anti-itch potential in clinical trials (
      • Guttman-Yassky E.
      • Silverberg J.I.
      • Nemoto O.
      • Forman S.B.
      • Wilke A.
      • Prescilla R.
      • et al.
      Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.
      ;
      • Kim B.S.
      • Howell M.D.
      • Sun K.
      • Papp K.
      • Nasir A.
      • Kuligowski M.E.
      • et al.
      Treatment of atopic dermatitis with Ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream.
      ;
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • Nagata T.
      Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study.
      ).

      Organization of murine itch-sensing primary afferent neurons

      The current model clusters itch-sensing primary afferents into several distinct populations on the basis of their gene expression profile, physiological properties, and function. Most of these neuronal populations are unmyelinated, small-diameter C-fiber DRG or trigeminal ganglia (TG) neurons, whose peripheral axons innervate the superficial layers of the skin, usually terminating as free nerve endings, and the central axons synapse with CNS neurons in the upper laminas of either the dorsal horn of the spinal cord or the spinal trigeminal nucleus (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ;
      • Morita T.
      • McClain S.P.
      • Batia L.M.
      • Pellegrino M.
      • Wilson S.R.
      • Kienzler M.A.
      • et al.
      HTR7 mediates serotonergic acute and chronic itch.
      ;
      • Patel K.N.
      • Dong X.
      Itch: Cells, molecules, and circuits.
      ). Unbiased single-cell RNA-sequencing studies of murine DRGs clustered itch sensing neurons into three widely referenced NP afferent populations: MRGPRD-expressing NP1 neurons, MRGPRA3-expressing NP2 neurons, and somatostatin/brain natriuretic peptide (NPPB)-expressing NP3 neurons (
      • Li C.
      • Wang S.
      • Chen Y.
      • Zhang X.
      Somatosensory neuron typing with high-coverage single-cell RNA sequencing and functional analysis.
      ;
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ;
      • Zeisel A.
      • Hochgerner H.
      • Lönnerberg P.
      • Johnsson A.
      • Memic F.
      • van der Zwan J.
      • et al.
      Molecular architecture of the mouse nervous system.
      ) (Figure 1 and Table 1). It should be noted that the NP nomenclature/classification stems from their lack of substance P (SP) or calcitonin gene-related peptide (CGRP) expression during late embryonic development (
      • Woolf C.J.
      • Ma Q.
      Nociceptors--noxious stimulus detectors.
      ). NP neurons express neuropeptides, many of which such as NPPB or GRP are largely itch specific in the spinal cord (
      • Dong X.
      • Dong X.
      Peripheral and central mechanisms of itch.
      ).
      Table 1Organization of Murine Itch Sensing DRG Neuron
      Neuronal ClusterNP1NP2NP3Unclassified
      Classification for this neuronal cluster has not been determined.
      NF1/NF2 LTMR (subset)
      Neuron typeC-fiberC-fiberC-fiberC-fiber
      Identifying molecular markerMRGPRDMRGPRA3SST/BNPTSLPRTLR5
      Histamine receptor status(–)HRH1HRH4(–)(–)
      MRGPR status(+)Multiple(–)?(–)(–)
      Serotonin receptor status(–)(–)HTR2, HTR7(–)(–)
      TLR status(–)TLR3?, TLR7?(–)(–)TLR5
      PAR status(–)(+)(–)(–)(–)
      IL receptor statusIL4R/IL13RIL4R/IL13R,

      ST2
      IL4R/IL13R,

      IL31R
      TSLPR(–)
      TRP statusTRPA1, TRPC3, TRPM3,TRPA1, TRPV1TRPA1, TRPV1TRPA1?
      Exogenous pruritogen sensitivityβ-alanineChloroquine,

      Defensins, proteases
      ??Flagellin, mechanical stimuli
      Chronic itch participationACDXerosis, ADADADXerosis, ACD, AD (mechanical alloknesis)
      Abbreviations: ACD, allergic contact dermatitis; AD, atopic dermatitis; HTR, 5-hydroxytryptamine receptor; LTMR, low threshold mechanoreceptor; NF, neurofilament; NP, nonpeptidergic; TLR, toll-like receptor.
      Classification for this neuronal cluster has not been determined.
      NP1 neurons were first identified as mechanoreceptors that detect punctate mechanical pain (
      • Cavanaugh D.J.
      • Lee H.
      • Lo L.
      • Shields S.D.
      • Zylka M.J.
      • Basbaum A.I.
      • et al.
      Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli [published correction appears in Proc Natl Acad Sci USA 2009;106:11424].
      ;
      • Dussor G.
      • Zylka M.J.
      • Anderson D.J.
      • McCleskey E.W.
      Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors.
      ). These neurons form the largest of the three clusters, making up approximately 20% of murine primary afferents in the DRG and TG (
      • Cavanaugh D.J.
      • Lee H.
      • Lo L.
      • Shields S.D.
      • Zylka M.J.
      • Basbaum A.I.
      • et al.
      Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli [published correction appears in Proc Natl Acad Sci USA 2009;106:11424].
      ;
      • Wang H.
      • Zylka M.J.
      Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons.
      ;
      • Zylka M.J.
      • Rice F.L.
      • Anderson D.J.
      Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd.
      ,
      • Zylka M.J.
      • Dong X.
      • Southwell A.L.
      • Anderson D.J.
      Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family.
      ). Since then, this population has been implicated in the acute itch induced by the bodybuilding supplement β-alanine, which directly activates MRGPRD receptors to induce nonhistaminergic itch (
      • Liu Q.
      • Sikand P.
      • Ma C.
      • Tang Z.
      • Han L.
      • Li Z.
      • et al.
      Mechanisms of itch evoked by β-alanine.
      ;
      • Shinohara T.
      • Harada M.
      • Ogi K.
      • Maruyama M.
      • Fujii R.
      • Tanaka H.
      • et al.
      Identification of a G protein-coupled receptor specifically responsive to beta-alanine.
      ). More recently, these neurons were implicated in ACD-associated pruritus, although the mechanism remains undefined (
      • Meixiong J.
      • Anderson M.
      • Limjunyawong N.
      • Sabbagh M.F.
      • Hu E.
      • Mack M.R.
      • et al.
      Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch.
      ;
      • Qu L.
      • Fan N.
      • Ma C.
      • Wang T.
      • Han L.
      • Fu K.
      • et al.
      Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain.
      ). Moreover, NP1 neurons express IL-4Rα/IL-13Rα1 receptors and the lysophosphatidic acid receptors LPAR3 and LPAR5 (
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ), suggesting potential involvement in other chronic itch conditions.
      NP2 neurons are perhaps the best studied itch-sensing population and are broadly implicated in both histaminergic and nonhistaminergic acute itch and chronic pruritus (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ;
      • Nattkemper L.A.
      • Tey H.L.
      • Valdes-Rodriguez R.
      • Lee H.
      • Mollanazar N.K.
      • Albornoz C.
      • et al.
      The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch.
      ;
      • Zhu Y.
      • Hanson C.E.
      • Liu Q.
      • Han L.
      Mrgprs activation is required for chronic itch conditions in mice.
      ). These neurons are principally responsible for detecting histamine through their HRH1 receptors (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ). In addition, NP1 neurons detect the antimalarial drug chloroquine through direct activation of their MRGPRA3 receptors (
      • Liu Q.
      • Tang Z.
      • Surdenikova L.
      • Kim S.
      • Patel K.N.
      • Kim A.
      • et al.
      Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
      ), and are broadly sensitive to both exogenous and endogenous itch mediators through their highly promiscuous MRGPRC11 receptor (
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ). Moreover, this population is frequently implicated in chronic itch conditions, including xerosis and AD (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ;
      • Qu L.
      • Fan N.
      • Ma C.
      • Wang T.
      • Han L.
      • Fu K.
      • et al.
      Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain.
      ;
      • Zhu Y.
      • Hanson C.E.
      • Liu Q.
      • Han L.
      Mrgprs activation is required for chronic itch conditions in mice.
      ), and was recently implicated in cholestatic itch through its MRGPRA1 receptors (
      • Meixiong J.
      • Vasavda C.
      • Green D.
      • Zheng Q.
      • Qi L.
      • Kwatra S.G.
      • et al.
      Identification of a bilirubin receptor that may mediate a component of cholestatic itch.
      ). Similar to NP1 neurons, NP2 neurons express IL-4Rα/IL-13Rα1 receptors and are sensitive to type 2 immune cell‒derived ILs, but may also be sensitive to KC-derived IL-33 through ST2 receptors (
      • Liu B.
      • Tai Y.
      • Achanta S.
      • Kaelberer M.M.
      • Caceres A.I.
      • Shao X.
      • et al.
      IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.
      ).
      NP3 neurons also show broad involvement in itch detection (
      • Emery E.C.
      • Ernfors P.
      Dorsal root ganglion neuron types and their functional specialization.
      ;
      • Huang J.
      • Polgár E.
      • Solinski H.J.
      • Mishra S.K.
      • Tseng P.Y.
      • Iwagaki N.
      • et al.
      Circuit dissection of the role of somatostatin in itch and pain [published correction appears in Nat Neurosci 2018;21:894].
      ) and share some functional overlap with NP2 neurons through their HRH4 and IL-4Rα/IL-13Rα1 receptors (
      • Usoskin D.
      • Furlan A.
      • Islam S.
      • Abdo H.
      • Lönnerberg P.
      • Lou D.
      • et al.
      Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
      ). Nevertheless, NP3 neurons possess considerable unique functions. These neurons are sensitive to T4 lymphocyte‒derived IL-31 through IL-31-Rα/OSMRβ receptor and are largely responsible for the detection of serotonergic itch through its HTR2 and HTR7 receptors (
      • Morita T.
      • McClain S.P.
      • Batia L.M.
      • Pellegrino M.
      • Wilson S.R.
      • Kienzler M.A.
      • et al.
      HTR7 mediates serotonergic acute and chronic itch.
      ). Recently, NP3 neurons were further implicated in two unique chronic itch processes. This population was reported to detect KC-derived periostin through its Av-β3 receptors during allergy and in a murine AD model (
      • Mishra S.K.
      • Wheeler J.J.
      • Pitake S.
      • Ding H.
      • Jiang C.
      • Fukuyama T.
      • et al.
      Periostin activation of integrin receptors on sensory neurons induces allergic itch.
      ). These neurons are also sensitive to basophil-derived cysteinyl leukotriene (LTC4) through its CYSLTR2 receptors and mediate allergic itch flares in AD (
      • Wang F.
      • Trier A.M.
      • Li F.
      • Kim S.
      • Chen Z.
      • Chai J.N.
      • et al.
      A basophil-neuronal axis promotes itch.
      ).
      In addition to the NP neurons, two additional groups of primary afferents are implicated in itch detection. IL7Rα/TSLPR-expressing C-fibers and a subset of neurofilament containing Aβ low-threshold mechanoreceptors (LTMRs) expressing TLR5 have been reported to mediate TSLP itch and mechanical itch, respectively (
      • Duan B.
      • Cheng L.
      • Ma Q.
      Spinal circuits transmitting mechanical pain and itch.
      ;
      • Wilson S.R.
      • Thé L.
      • Batia L.M.
      • Beattie K.
      • Katibah G.E.
      • McClain S.P.
      • et al.
      The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
      ). However, these afferent populations are not as well-characterized, and the extent of their functions in itch detection has not been fully defined.

      Evolutionary conservation of itch neuron anatomy

      It should be noted that colocalization of known pruritogen-sensing receptors is variable between species, even among rodents (
      • Han L.
      • Dong X.
      Itch mechanisms and circuits.
      ;
      • Zylka M.J.
      • Dong X.
      • Southwell A.L.
      • Anderson D.J.
      Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family.
      ). Owing to limitations in and the technical difficulties associated with studies involving human or nonhuman primate sensory neurons, genetic and functional characterization of human itch afferents remain largely incomplete. Because of this, it is not certain whether the organization of human and murine itch-sensing primary afferent populations shares a high degree of anatomical or genetic conservation. Nevertheless, the limited available evidence has thus far supported the notion that this process is well-conserved between mice and humans. Although there are some notable differences, the expression pattern of itch-related receptors in human sensory neurons is largely similar to what is observed in mice. MRGPRs, HRH, HTRs, and IL4/13/31 receptors are expressed by human DRGs, even though the exact distribution of these receptors across human DRG populations remains undefined (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ;
      • Ray P.
      • Torck A.
      • Quigley L.
      • Wangzhou A.
      • Neiman M.
      • Rao C.
      • et al.
      Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research.
      ). Moreover, MRGPRD and MRGPRX1 expression can be used to define two distinct populations of C-fiber neurons in human DRGs, where the latter group is also sensitive to chloroquine, MRGPRC11 agonists, and histamine (
      • Valtcheva M.V.
      • Copits B.A.
      • Davidson S.
      • Sheahan T.D.
      • Pullen M.Y.
      • McCall J.G.
      • et al.
      Surgical extraction of human dorsal root ganglia from organ donors and preparation of primary sensory neuron cultures.
      ). These two human primary afferent populations could represent the functional homologous of murine NP1 and NP2 neurons, respectively. Additional studies are needed to confirm whether this is the case.
      Despite the unknowns, human and murine pruritogen receptors often form clear homologous pairs and show remarkable functional conservation in their ability to detect exogenous pruritogens (
      • Meixiong J.
      • Dong X.
      Mas-related G protein–coupled receptors and the biology of itch sensation.
      ). Moreover, clinical features of murine and human itch pathologies are highly similar; even the antihistamine-refractory nature of many chronic itch skin pathologies is conserved between the species. Because of these features and the broad availability of genetic mutants, murine models have been ideal for the study of both acute itch and translational studies of chronic pathologies involving pruritus.

      Neuronal itch initiation

      Although itch is often initiated by immune or epidermal cells, all the peripheral itch signals, including both endogenous and exogenous, are detected and transmitted centrally by primary sensory neurons. As mentioned in the previous section, murine NP1 and NP2 neurons directly detect pruritogens β-alanine and chloroquine through their hallmark MRGPR receptors, MRGPRD and MRGPRA3, respectively (
      • Liu Q.
      • Sikand P.
      • Ma C.
      • Tang Z.
      • Han L.
      • Li Z.
      • et al.
      Mechanisms of itch evoked by β-alanine.
      ,
      • Liu Q.
      • Tang Z.
      • Surdenikova L.
      • Kim S.
      • Patel K.N.
      • Kim A.
      • et al.
      Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
      ). More recent studies have shown that tick defensin peptides IPDef1 and IRDef2 and the dust mite cysteine protease Der p1 directly activate NP2 neurons through MRGPRC11 receptors (
      • Li X.
      • Yang H.
      • Han Y.
      • Yin S.
      • Shen B.
      • Wu Y.
      • et al.
      Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors.
      ;
      • Serhan N.
      • Basso L.
      • Sibilano R.
      • Petitfils C.
      • Meixiong J.
      • Bonnart C.
      • et al.
      House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation.
      ). These functions are conserved in humans through the MRGPRD and MRGPRX1 receptors (
      • Huang C.H.
      • Kuo I.C.
      • Xu H.
      • Lee Y.S.
      • Chua K.Y.
      Mite allergen induces allergic dermatitis with concomitant neurogenic inflammation in mouse.
      ;
      • Li X.
      • Yang H.
      • Han Y.
      • Yin S.
      • Shen B.
      • Wu Y.
      • et al.
      Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors.
      ;
      • Liu Q.
      • Sikand P.
      • Ma C.
      • Tang Z.
      • Han L.
      • Li Z.
      • et al.
      Mechanisms of itch evoked by β-alanine.
      ,
      • Liu Q.
      • Tang Z.
      • Surdenikova L.
      • Kim S.
      • Patel K.N.
      • Kim A.
      • et al.
      Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
      ).
      Two recent studies independently implicated MRGPRX4 receptors in neurogenic cholestatic itch (
      • Meixiong J.
      • Vasavda C.
      • Snyder S.H.
      • Dong X.
      MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus.
      ;
      • Yu H.
      • Zhao T.
      • Liu S.
      • Wu Q.
      • Johnson O.
      • Wu Z.
      • et al.
      MRGPRX4 is a bile acid receptor for human cholestatic itch.
      ). Enhanced serotonergic and MRGPR signaling as well as neuronal TGR5 receptor activation had already been associated with cholestatic itch (
      • Alemi F.
      • Kwon E.
      • Poole D.P.
      • Lieu T.
      • Lyo V.
      • Cattaruzza F.
      • et al.
      The TGR5 receptor mediates bile acid-induced itch and analgesia.
      ;
      • Sanjel B.
      • Maeng H.J.
      • Shim W.S.
      BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus.
      ;
      • Schwörer H.
      • Hartmann H.
      • Ramadori G.
      Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron.
      ). These new studies further show that the human MRGPRX4 receptor, which is expressed by histamine-sensitive itch-sensing DRG neurons, is directly activated by bilirubin and bile acid components, especially deoxycholate. Bilirubin was further demonstrated to activate mouse MRGPRA1 receptors and NP2 neurons; however, the mouse neuronal receptor for deoxycholate remains unidentified (
      • Meixiong J.
      • Vasavda C.
      • Green D.
      • Zheng Q.
      • Qi L.
      • Kwatra S.G.
      • et al.
      Identification of a bilirubin receptor that may mediate a component of cholestatic itch.
      ,
      • Meixiong J.
      • Vasavda C.
      • Snyder S.H.
      • Dong X.
      MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus.
      ;
      • Yu H.
      • Zhao T.
      • Liu S.
      • Wu Q.
      • Johnson O.
      • Wu Z.
      • et al.
      MRGPRX4 is a bile acid receptor for human cholestatic itch.
      ). A third study further showed epithelial involvement in cholestatic itch, which will be discussed later in this review (
      • Chen Y.
      • Wang Z.L.
      • Yeo M.
      • Zhang Q.J.
      • López-Romero A.E.
      • Ding H.P.
      • et al.
      Epithelia-sensory neuron cross talk underlies cholestatic itch induced by lysophosphatidylcholine.
      ).

      Mechanical itch detection

      Mechanically evoked itch, such as that from a bug walking across the skin or light prickling of a von Frey hair on a laboratory mouse, was recently reported to be mediated by a subpopulation of TLR5-expressing Aβ LTMRs (Figure 2a)—this same population may also directly detect flagellin-induced acute itch. Silencing of these neurons blocked both acutely induced mechanical itch within their receptive field as well as eliminated histamine-induced mechanical alloknesis. Interestingly, silencing of these neurons or their postsynaptic spinal circuits in mice also attenuated mechanical alloknesis and spontaneous itch across a range of pruritic skin conditions, including acetone:ether water (AEW) model of xerosis, ACD, and AD (
      • Duan B.
      • Cheng L.
      • Ma Q.
      Spinal circuits transmitting mechanical pain and itch.
      ;
      • Pan H.
      • Fatima M.
      • Li A.
      • Lee H.
      • Cai W.
      • Horwitz L.
      • et al.
      Identification of a spinal circuit for mechanical and persistent spontaneous itch.
      ). However, the precise mechanism of neural gating of mechanical itch in the CNS appears quite complex. Loss or silencing of Aβ LTMRs in other contexts has also, paradoxically, been reported to enhance mechanical alloknesis (
      • Sakai K.
      • Akiyama T.
      Disinhibition of touch-evoked itch in a mouse model of psoriasis.
      ). Furthermore, in aging mice, the loss of touch-sensitive Merkel cells, one of the many touch-sensitive skin structures that complexes with Aβ LTMRs, was correlated with increased mechanical allokinesis and hyperkinesis (
      • Feng J.
      • Luo J.
      • Yang P.
      • Du J.
      • Kim B.S.
      • Hu H.
      Piezo2 channel–Merkel cell signaling modulates the conversion of touch to itch.
      ). Additional studies are required to further delineate the mechanical itch mechanism as well as the overlap of mechanical and chemical itch-processing circuits in the CNS.
      Figure thumbnail gr2
      Figure 2Mechanisms of chronic itch. (a) Age-related loss of touch-sensitive Merkel cells is associated with increased mechanical hyperkinesis. However, loss of TLR5 Aβ-LTMRs that detect mechanical itch leads to loss of mechanical itch sensitivity and attenuation of chronic itch. (b) The current understanding of CTCL itch occurs through two main pathways. First, IL-31 released by neoplastic T cells can directly activate neuronal itch receptors, whereas IL-4, IL-2, and IL-6 enhance itch. (c) Psoriasis-associated itch mechanisms are not completely understood. Endogenous pruritogens, including IL-31, TSLP, and mast cell‒derived PGE2 and ET1, have all been implicated; whereas NGF and type 2 cytokines may further potentiate itch by enhancing neuronal excitability. (d) AD-associated itch is primarily generated by type 2 cytokine‒induced itch neuron excitability and reciprocal modulation by neurons. Endogenous pruritogens, released by immune cells and keratinocytes, include peptides; proteases; and mast cell‒, basophil-, and ILC2-derived factors. AD, atopic dermatitis; CGRP, calcitonin gene-related peptide; CTCL, cutaneous T-cell lymphoma; DC, dendritic cell; ILC, innate lymphoid cell; KLK, kallikrein; LC, Langerhans cell; LTC4, leukotriene C4; NP, nonpeptidergic; SP, substance P; Th, T helper; TLR, toll-like receptor. Illustration assistance provided by Ruvido Medical Illustration.

      Neuroimmune and neural‒epidermal mechanisms of pruritogen detection

      Mast cells

      Whereas most types of innate immune cells and T cells are involved in itch in some capacity, mast cells are the standouts in terms of itch functions and have been implicated in many pruritic skin diseases (
      • Meixiong J.
      • Basso L.
      • Dong X.
      • Gaudenzio N.
      Nociceptor–mast cell sensory clusters as regulators of skin homeostasis.
      ;
      • Siiskonen H.
      • Harvima I.
      Mast cells and sensory nerves contribute to neurogenic inflammation and pruritus in chronic skin inflammation.
      ;
      • Wang F.
      • Kim B.S.
      Itch: a paradigm of neuroimmune crosstalk.
      ).
      The mast cell‒neuron complex is a highly conserved itch-sensing unit across mammalian species (Figure 1). Mast cells are closely associated with itch-sensing afferents in the skin (
      • Huang C.C.
      • Yang W.
      • Guo C.
      • Jiang H.
      • Li F.
      • Xiao M.
      • et al.
      Anatomical and functional dichotomy of ocular itch and pain.
      ) and are perhaps best known for their canonical role as the principal mediator of allergic urticaria and anaphylaxis (
      • Hennino A.
      • Bérard F.
      • Guillot I.
      • Saad N.
      • Rozières A.
      • Nicolas J.F.
      Pathophysiology of urticaria.
      ). During this process, allergens cross a damaged skin barrier and bind to mast cells through FcεRI receptor‒bound IgE antibodies. Subsequent crosslinking of IgE triggers rapid degranulation of the mast cells and the release of an inflammatory soup containing, among other things, endogenous itch mediators, including histamine and 5-HT, as well as newly discovered endogenous itch mediators such as neuropeptide FF, LTC4, and type 2 cytokines. In mice, these endogenous pruritogens converge on NP2 and NP3 neurons to induce itch (
      • Meixiong J.
      • Basso L.
      • Dong X.
      • Gaudenzio N.
      Nociceptor–mast cell sensory clusters as regulators of skin homeostasis.
      ;
      • Solinski H.J.
      • Kriegbaum M.C.
      • Tseng P.Y.
      • Earnest T.W.
      • Gu X.
      • Barik A.
      • et al.
      Nppb neurons are sensors of mast cell-induced itch.
      ;
      • Wang F.
      • Kim B.S.
      Itch: a paradigm of neuroimmune crosstalk.
      ).
      Conversely, murine mast cells respond to a range of neuropeptides, including SP and CGRP, released from the peripheral terminals of nociceptive and pruritoceptive DRG neurons (
      • Forsythe P.
      Mast cells in neuroimmune interactions.
      ;
      • Meixiong J.
      • Basso L.
      • Dong X.
      • Gaudenzio N.
      Nociceptor–mast cell sensory clusters as regulators of skin homeostasis.
      ). During steady states, these neuropeptides promote the close association of mast cells with nerve terminals; and during allergy, these peptides can trigger mast cell chemotaxis to the affected skin and directly modulate mast cell responses (
      • Kleij H.P.
      • Bienenstock J.
      Significance of conversation between mast cells and nerves.
      ;
      • Rogoz K.
      • Aresh B.
      • Freitag F.B.
      • Pettersson H.
      • Magnúsdóttir E.I.
      • Larsson Ingwall L.
      • et al.
      Identification of a neuronal receptor controlling anaphylaxis.
      ;
      • Xu H.
      • Shi X.
      • Li X.
      • Zou J.
      • Zhou C.
      • Liu W.
      • et al.
      Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review.
      ). In an extreme example, one study reported that mGluR7 deficiency in NP2 itch neurons, which disrupts glutamate-dependent autocrine-negative feedback at the central terminals of these neurons, led to exaggerated mast cell‒dependent itch and anaphylaxis responses during allergy (
      • Rogoz K.
      • Aresh B.
      • Freitag F.B.
      • Pettersson H.
      • Magnúsdóttir E.I.
      • Larsson Ingwall L.
      • et al.
      Identification of a neuronal receptor controlling anaphylaxis.
      ).
      The contribution of mast cells is not solely restricted to allergic histaminergic itch. In mice, the activation of mast cells alone through chemogenetics or its surface receptors (without concurrent allergy or inflammation) is sufficient to induce degranulation and subsequent itch (
      • Solinski H.J.
      • Kriegbaum M.C.
      • Tseng P.Y.
      • Earnest T.W.
      • Gu X.
      • Barik A.
      • et al.
      Nppb neurons are sensors of mast cell-induced itch.
      ). Importantly, mast cells express the murine MRGPRB2 receptor and its human homolog MRGPRX2 (
      • McNeil B.D.
      • Pundir P.
      • Meeker S.
      • Han L.
      • Undem B.J.
      • Kulka M.
      • et al.
      Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
      ;
      • Tatemoto K.
      • Nozaki Y.
      • Tsuda R.
      • Konno S.
      • Tomura K.
      • Furuno M.
      • et al.
      Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors.
      ). As mentioned previously, many MRGPRs are principally neuronal itch sensors, and mast cells are among the few non-neuronal tissues with MRGPR expression. Activation of MRGPRB2/X2 receptors can directly trigger mast cell degranulation, leading to nonhistaminergic itch, inflammation, and innate immune response (
      • McNeil B.D.
      • Pundir P.
      • Meeker S.
      • Han L.
      • Undem B.J.
      • Kulka M.
      • et al.
      Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
      ;
      • Yuan F.
      • Zhang C.
      • Sun M.
      • Wu D.
      • Cheng L.
      • Pan B.
      • et al.
      MRGPRX2 mediates immediate-type pseudo-allergic reactions induced by iodine-containing iohexol.
      ). Even though these receptors were only deorphaned within the past decade, MRGPRB2/X2 receptors have been shown to demonstrate broad sensitivity toward both endogenous and exogenous chemicals, including many neuropeptides and neuroendocrine secretory proteins (
      • Grimes J.
      • Desai S.
      • Charter N.W.
      • Lodge J.
      • Moita Santos R.
      • Isidro-Llobet A.
      • et al.
      MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo-allergic and anaphylactoid reactions.
      ;
      • McNeil B.D.
      • Pundir P.
      • Meeker S.
      • Han L.
      • Undem B.J.
      • Kulka M.
      • et al.
      Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
      ). These receptors also directly meditate drug-induced pseudoallergic reactions, including those caused by C48/80, atracurium, vancomycin, and a number of quinolone antibiotics (
      • Babina M.
      The pseudo-allergic/neurogenic route of mast cell activation via MRGPRX2: discovery, functional programs, regulation, relevance to disease, and relation with allergic stimulation.
      ;
      • McNeil B.D.
      • Pundir P.
      • Meeker S.
      • Han L.
      • Undem B.J.
      • Kulka M.
      • et al.
      Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
      ;
      • Meixiong J.
      • Vasavda C.
      • Snyder S.H.
      • Dong X.
      MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus.
      ;
      • Yuan F.
      • Zhang C.
      • Sun M.
      • Wu D.
      • Cheng L.
      • Pan B.
      • et al.
      MRGPRX2 mediates immediate-type pseudo-allergic reactions induced by iodine-containing iohexol.
      ).
      Recently, mast cells have also been implicated as a major effector of ACD-associated itch. ACD had been generally described as a Langerhans cell‒ and T-cell‒driven process. However,
      • Meixiong J.
      • Anderson M.
      • Limjunyawong N.
      • Sabbagh M.F.
      • Hu E.
      • Mack M.R.
      • et al.
      Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch.
      further reported that ACD-associated itch is primarily a mast cell‒dependent process. Although T-cell‒derived ILs undoubtedly rearrange the itch-sensing environment in the affected skin, MRGPRB2 deficiency significantly attenuated itch across multiple murine models of ACD. Moreover, the authors’ findings strongly suggest that ACD-associated itch is generated through a KC-mast cell mechanism. Under inflammatory skin conditions, KCs secrete PAM9–20, which activate mast cell MRGPRB2 receptors in a histamine- and IgE-independent manner. Activated mast cells, in turn, activate NP1 and, to a lesser extent, NP2, and NP3 neurons to elicit itch (
      • Meixiong J.
      • Anderson M.
      • Limjunyawong N.
      • Sabbagh M.F.
      • Hu E.
      • Mack M.R.
      • et al.
      Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch.
      ).

      T cells

      In addition to mast cells, cutaneous CD4+ T cells, especially Th2 cells, are increasingly recognized for their involvement in the pruriotgenic process. However, in contrast to mast cells, examples of direct T-cell involvement in acute itch detection or initiation are sparse because these cells are recruited by innate immune cells and arrive comparatively late in the allergen or pathogen response process. Instead, T-cell function in itch is much better understood in terms of their role in the chronic or dysfunctional remodeling of the itch-sensing microenvironment. T-cell‒derived cytokines are integrally involved in the initiation and continuance of cutaneous inflammation as well as the enhancement of itch neuron excitability. These effects are most prominently observed in chronically itchy inflammatory skin disorders such as psoriasis and AD, which will be discussed in greater detail in a later section.
      Nonetheless, T cells possess the ability to produce itch. The best example of T-cell‒driven itch is perhaps cutaneous T-cell lymphoma (CTCL) (Figure 2b). CTCL is a class of non‒Hodkin lymphoma characterized by the accumulation of neoplastic T cells in the skin. Severe itching of the affected skin is commonly associated with advanced-stage disease, which typically cannot be satisfactorily alleviated by steroids or antihistamines (
      • Ahern K.
      • Gilmore E.S.
      • Poligone B.
      Pruritus in cutaneous T-cell lymphoma: a review.
      ;
      • Meyer N.
      • Paul C.
      • Misery L.
      Pruritus in cutaneous T-cell lymphomas: frequent, often severe and difficult to treat.
      ;
      • Misery L.
      Chapter 8: Pruritus in cutaneous T-cell lymphomas.
      ;
      • Vij A.
      • Duvic M.
      Prevalence and severity of pruritus in cutaneous T cell lymphoma.
      ). The pathophysiology of CTCL-associated itch is complex and is not completely understood. Previous studies of CTCL tissues have typically reported Th2-like secretory profiles in the malignant cells and elevated Th2-derived cytokine levels in the affected epidermis and serums of patients with CTCL with pruritus. Moreover, this Th2 polarization was more prominent with disease progression (
      • Nattkemper L.A.
      • Martinez-Escala M.E.
      • Gelman A.B.
      • Singer E.M.
      • Rook A.H.
      • Guitart J.
      • et al.
      Cutaneous T-cell lymphoma and pruritus: the expression of IL-31 and its receptors in the skin.
      ;
      • Singer E.M.
      • Shin D.B.
      • Nattkemper L.A.
      • Benoit B.M.
      • Klein R.S.
      • Didigu C.A.
      • et al.
      IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus.
      ). As mentioned previously, receptors for Th2-derived cytokines are broadly expressed across all the three NP itch-sensing neuron populations. Intradermal IL-31 injection acutely induces itch in naive mice through NP3 neurons, whereas IL-4 injection acutely potentiates histamine-induced itch (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ). Elevated IL-4 and IL-31 are both associated with CTCL, and serum IL-31 level is directly correlated with CTCL itch severity (
      • Cedeno-Laurent F.
      • Singer E.M.
      • Wysocka M.
      • Benoit B.M.
      • Vittorio C.C.
      • Kim E.J.
      • et al.
      Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities.
      ;
      • Singer E.M.
      • Shin D.B.
      • Nattkemper L.A.
      • Benoit B.M.
      • Klein R.S.
      • Didigu C.A.
      • et al.
      IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus.
      ). IL-2 and IL-6 are also reported to be elevated in patients with CTCL and may further contribute to itch through less direct mechanisms (
      • Misery L.
      Chapter 8: Pruritus in cutaneous T-cell lymphomas.
      ).
      More recently, one study reported T-cell‒derived microRNA (miR) involvement in a mouse CTCL chronic itch model (
      • Han Q.
      • Liu D.
      • Convertino M.
      • Wang Z.
      • Jiang C.
      • Kim Y.H.
      • et al.
      miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus.
      ). In itch biology, transient receptor potential channels are mainly referenced in their role as signal transduction channels for upstream GPCRs. The TRPV1 channel, for example, is critically required for HRH signal propagation (
      • Shim W.S.
      • Tak M.H.
      • Lee M.H.
      • Kim M.
      • Kim M.
      • Koo J.Y.
      • et al.
      TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase.
      ), and the TRPA1 channel is required for several MRGPRs (
      • Dong X.
      • Dong X.
      Peripheral and central mechanisms of itch.
      ). Most of these channels are temperature sensitive and ligand gated and, owing to their functions as nonselective cation channels, can directly produce membrane depolarization in neurons upon opening. In the study mentioned earlier, the author reported that miR-711 secreted by CTCL tumor directly activates neuronal TRPA1 channels, presumably through NP2 neurons, to produce itch. Moreover, the authors report that inhibition of this miR, TRPA1 antagonism, or the use of a blocking peptide can all acutely alleviate chronic itch in their CTCL mouse model (
      • Han Q.
      • Liu D.
      • Convertino M.
      • Wang Z.
      • Jiang C.
      • Kim Y.H.
      • et al.
      miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus.
      ).

      KCs

      In addition to immune cells, KCs also respond to a range of external and endogenous stimuli. Upon activation, these cells release both acute endogenous itch mediators as well as inflammatory and neurotropic factors that remodel the itch-sensing environment. Proteases such as mucunain (cowhedge) and Der p1 (dust mite) can directly cleave KC PAR2 receptors, leading to the release of endogenous itch mediators such as SLIGRL-NH2/SLIGKV-NH2 and the extracellular matrix protein periostin. In turn, these compounds activate the neuronal itch receptors MRGPRC11/X1 (NP2) and Av-β3 integrin receptors (NP3), respectively (
      • Akiyama T.
      • Lerner E.A.
      • Carstens E.
      Protease-activated receptors and itch.
      ;
      • Kouzaki H.
      • O’Grady S.M.
      • Lawrence C.B.
      • Kita H.
      Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2.
      ;
      • Mishra S.K.
      • Wheeler J.J.
      • Pitake S.
      • Ding H.
      • Jiang C.
      • Fukuyama T.
      • et al.
      Periostin activation of integrin receptors on sensory neurons induces allergic itch.
      ;
      • Moniaga C.S.
      • Jeong S.K.
      • Egawa G.
      • Nakajima S.
      • Hara-Chikuma M.
      • Jeon J.E.
      • et al.
      Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.
      ;
      • Steinhoff M.
      • Neisius U.
      • Ikoma A.
      • Fartasch M.
      • Heyer G.
      • Skov P.S.
      • et al.
      Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.
      ;
      • Tong Q.
      • Ye C.P.
      • McCrimmon R.J.
      • Dhillon H.
      • Choi B.
      • Kramer M.D.
      • et al.
      Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia.
      ). KC TLR activation presumably elicits itch in a similar manner. In addition to exogenous irritants, KCs also respond to a range of inflammatory signals from neighboring KCs and cytokines and proteases from immune cells to produce itch in a similar manner.
      In addition, KCs and their TRPV4 channels are principally important for development of xerosis-associated itch. TRPV4 is activated by hypoosmolarity (
      • Liedtke W.
      • Friedman J.M.
      Abnormal osmotic regulation in trpv4–/– mice.
      ). Consistent with this, TRPV4 deficiency in KCs has been reported to significantly attenuate chronic itch in the murine AEW-induced xerosis model (
      • Luo J.
      • Feng J.
      • Yu G.
      • Yang P.
      • Mack M.R.
      • Du J.
      • et al.
      Transient receptor potential vanilloid 4–expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.
      ), which disrupts the lipid barrier with acetone and ether and repeatedly exposes KCs to hypoosmolarity of deionized water. However, the connection between KCs and itch-sensing neurons in this model and for xerosis, in general, is not completely understood. There is no known immune involvement (
      • Miyamoto T.
      • Nojima H.
      • Shinkado T.
      • Nakahashi T.
      • Kuraishi Y.
      Itch-associated response induced by experimental dry skin in mice.
      ), but AEW treatment induces notable physiological changes in the affected skin and MRGPR overexpression in NP2 neurons (
      • Zhu Y.
      • Hanson C.E.
      • Liu Q.
      • Han L.
      Mrgprs activation is required for chronic itch conditions in mice.
      ). Moreover, loss of NP2 neurons almost completely abolishes AEW itch, suggesting a possible KC‒MRGPR mechanism (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ). A recent study further reported that neuron-specific deletion of IL-33R resulted in dramatically attenuated itch in the AEW model (
      • Trier A.M.
      • Mack M.R.
      • Fredman A.
      • Tamari M.
      • Ver Heul A.M.
      • Zhao Y.
      • et al.
      IL-33 signaling in sensory neurons promotes dry skin itch [e-pub ahead of print].
      ). IL-33R is broadly expressed by NP2 neurons, but IL-33 itself is not known to be pruritogenic. Although it remains to be determined whether IL-33 can directly induce itch in xerotic skin, this finding strongly suggests that IL-33 released by damaged KCs augments NP2 neuron excitability. Indeed, this same study noted that IL-33 may acutely promote chloroquine response in cultured mouse DRG neurons (
      • Trier A.M.
      • Mack M.R.
      • Fredman A.
      • Tamari M.
      • Ver Heul A.M.
      • Zhao Y.
      • et al.
      IL-33 signaling in sensory neurons promotes dry skin itch [e-pub ahead of print].
      ). Our own research is currently focused on identifying KC-derived MRGPR agonists, with promising progress.
      Another recently published study further showed the involvement of KC TRPV4 channels in cholestatic itch (
      • Chen Y.
      • Wang Z.L.
      • Yeo M.
      • Zhang Q.J.
      • López-Romero A.E.
      • Ding H.P.
      • et al.
      Epithelia-sensory neuron cross talk underlies cholestatic itch induced by lysophosphatidylcholine.
      ). In this study, the authors reported that lysophosphatidylcholine, the LPA precursor, directly activates mouse KCs through their TRPV4 channels and triggers the secretion of miR-146a, which in turn acts on sensory neurons to produce itch. However, the exact neuronal receptor for miR-146a remains to be determined (
      • Chen Y.
      • Wang Z.L.
      • Yeo M.
      • Zhang Q.J.
      • López-Romero A.E.
      • Ding H.P.
      • et al.
      Epithelia-sensory neuron cross talk underlies cholestatic itch induced by lysophosphatidylcholine.
      ). Neuronal TRPV1 channels were shown to be required for signal propagation, whereas TRPA1 and TLRs, which were previously highlighted in the detection of pruritogenic single-strand RNAs (
      • Diebold S.S.
      Recognition of viral single-stranded RNA by toll-like receptors.
      ;
      • Han Q.
      • Liu D.
      • Convertino M.
      • Wang Z.
      • Jiang C.
      • Kim Y.H.
      • et al.
      miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus.
      ), were dispensable in this setting.

      Mechanism of psoriasis and AD itch

      Because of the prevalence of psoriasis and AD, intense psychophysical impacts on patients, and often treatment-refractory nature of these disorders, intense research efforts have been invested to decipher their mechanisms and to identify new therapeutic targets. The clinical presentations of psoriasis and AD are similar, that is, dry, inflamed skin with intense pruritus. These disorders are also both antihistamine refractory, with complex involvement and convergence of the dermal, immune, and neuronal components mentioned earlier. In addition, sensitization of CNS itch circuits is also associated with both psoriasis and AD. Despite the similarities, these two disorders are driven by different immunological and itch mechanisms, which are described in Figure 2c and d (
      • Kapur S.
      • Watson W.
      • Carr S.
      Atopic dermatitis.
      ;
      • Rendon A.
      • Schäkel K.
      Psoriasis pathogenesis and treatment.
      ).
      The mechanism behind psoriasis-associated itch is still not well-understood, largely owing to the complexity of the disorder and the fact that psoriasis is unique to humans. No single mouse model has fully recapitulated human psoriasis disease (
      • Schön M.P.
      • Manzke V.
      • Erpenbeck L.
      Animal models of psoriasis—highlights and drawbacks.
      ). Nevertheless, some contributing factors are known. Although psoriasis is a Th1/Th17-driven process, TSLP and the Th2 cytokine IL-31 are reported to be elevated in psoriatic skin (
      • Komiya E.
      • Tominaga M.
      • Kamata Y.
      • Suga Y.
      • Takamori K.
      Molecular and cellular mechanisms of itch in psoriasis.
      ;
      • Nattkemper L.A.
      • Tey H.L.
      • Valdes-Rodriguez R.
      • Lee H.
      • Mollanazar N.K.
      • Albornoz C.
      • et al.
      The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch.
      ;
      • Volpe E.
      • Pattarini L.
      • Martinez-Cingolani C.
      • Meller S.
      • Donnadieu M.H.
      • Bogiatzi S.I.
      • et al.
      Thymic stromal lymphopoietin links keratinocytes and dendritic cell–derived IL-23 in patients with psoriasis.
      ) and induce itch through direct activation of neuronal itch receptors. Histamine and mast cells are also abundantly present in psoriatic skin. However, existing studies have not consistently correlated histamine or HRH levels with itch (
      • Jaworecka K.
      • Muda-Urban J.
      • Rzepko M.
      • Reich A.
      Molecular aspects of pruritus pathogenesis in psoriasis.
      ), and psoriasis itch is rarely treatable using antihistamines. The neuropeptide SP and its receptor NK1R (which is expressed by KCs, immune cells, and neurons) levels are also frequently reported to be elevated in psoriatic skin (
      • Komiya E.
      • Tominaga M.
      • Kamata Y.
      • Suga Y.
      • Takamori K.
      Molecular and cellular mechanisms of itch in psoriasis.
      ;
      • Saraceno R.
      • Kleyn C.E.
      • Terenghi G.
      • Griffiths C.E.
      The role of neuropeptides in psoriasis.
      ). Promisingly, the NK1R antagonist serlopitant recently completed phase 2 trials and reported mild attenuation of psoriasis itch (
      • Pariser D.M.
      • Bagel J.
      • Lebwohl M.
      • Yosipovitch G.
      • Chien E.
      • Spellman M.C.
      Serlopitant for psoriatic pruritus: a phase 2 randomized, double-blind, placebo-controlled clinical trial.
      ). However, the interpretation of this finding is difficult because SP signaling is involved in both ascending and descending itch circuits in the CNS (
      • Ständer S.
      • Yosipovitch G.
      Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus.
      ), and this trial did not exclude CNS effects. In addition, nerve GF (NGF), prostaglandin E2 (PGE2), endothelin-1 (ET-1), and κ-opioid receptor (KOR)–all of which, except for KOR–were specifically increased in lesional skin, which was decreased. PGE2 and ET-1 are both putative itch mediators, NGF has been suggested to promote itch by inducing hyperinnervation of skin nerve fibers, and KOR and its ligand dynorphin A have been reported to suppress itch but only in the context of the CNS (
      • Jaworecka K.
      • Muda-Urban J.
      • Rzepko M.
      • Reich A.
      Molecular aspects of pruritus pathogenesis in psoriasis.
      ;
      • Komiya E.
      • Tominaga M.
      • Kamata Y.
      • Suga Y.
      • Takamori K.
      Molecular and cellular mechanisms of itch in psoriasis.
      ).
      Similar to psoriasis, AD itch is also a complex, multifaceted process with no shortage of pruritogens. There is some overlap with psoriasis because TSLP, IL-31, SP, NGF, opioid receptors, among others have also been implicated in AD pruritus. In addition, proteases such as cathepsin and tryptase have also been previously shown to contribute to AD itch (
      • Mollanazar N.K.
      • Smith P.K.
      • Yosipovitch G.
      Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
      ). More recently, epidermally derived periostin and basophil-derived LTC4 have been reported to promote AD itch by direct activation of murine NP3 neurons through AvB3 and CYSLTR2 receptors, respectively (
      • Mishra S.K.
      • Wheeler J.J.
      • Pitake S.
      • Ding H.
      • Jiang C.
      • Fukuyama T.
      • et al.
      Periostin activation of integrin receptors on sensory neurons induces allergic itch.
      ;
      • Wang F.
      • Trier A.M.
      • Li F.
      • Kim S.
      • Chen Z.
      • Chai J.N.
      • et al.
      A basophil-neuronal axis promotes itch.
      ). The basophil axis is especially relevant during allergy-triggered acute itch flares. Our own study recently implicated the KC-derived serine protease kallikrein 7 as another important contributor of itch in mouse AD-like disease through an immune-independent mechanism (
      • Guo C.J.
      • Mack M.R.
      • Oetjen L.K.
      • Trier A.M.
      • Council M.L.
      • Pavel A.B.
      • et al.
      Kallikrein 7 promotes atopic dermatitis-associated itch independently of skin inflammation.
      ).
      Arguably, the most important discovery in relation to AD-associated itch has been the identification of Th2 receptor‒mediated potentiation of neuronal excitability (
      • Meng J.
      • Li Y.
      • Fischer M.J.M.
      • Steinhoff M.
      • Chen W.
      • Wang J.
      Th2 modulation of transient receptor potential channels: an unmet therapeutic intervention for atopic dermatitis.
      ;
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ). IL-4R/IL-13R is expressed by all the three NP itch-sensing afferents groups, and IL-31R is expressed in serotonin-sensitive NP3 neurons, which detect periostin and LTC4 itch signals. Even though Th2 cytokines are weak acute pruritogens, neuron-specific deletion of IL-4Rα receptor subunits significantly attenuated AD itch in mice (
      • Oetjen L.K.
      • Mack M.R.
      • Feng J.
      • Whelan T.M.
      • Niu H.
      • Guo C.J.
      • et al.
      Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
      ). Moreover, these same mice showed reduced skin disease severity, strongly suggesting that reciprocal neuronal modulation of immune populations is another major driver of this disorder. Consistent with these results, anti–IL-4 therapy have shown great efficacy in alleviating AD symptoms, including itch, in patients with moderate to severe AD (
      • Beck L.A.
      • Thaçi D.
      • Hamilton J.D.
      • Graham N.M.
      • Bieber T.
      • Rocklin R.
      • et al.
      Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.
      ;
      • Silverberg J.I.
      • Yosipovitch G.
      • Simpson E.L.
      • Kim B.S.
      • Wu J.J.
      • Eckert L.
      • et al.
      Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS.
      ). Jak1 inhibitors, which target the common intracellular signaling of IL4R, IL-31R, and TSLPR, are likewise showing great promise in clinical trials (
      • Kim B.S.
      • Howell M.D.
      • Sun K.
      • Papp K.
      • Nasir A.
      • Kuligowski M.E.
      • et al.
      Treatment of atopic dermatitis with Ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream.
      ;
      • Scuron M.D.
      • Fay B.L.
      • Connell A.J.
      • Peel M.T.
      • Smith P.A.
      Ruxolitinib cream has dual efficacy on pruritus and inflammation in experimental dermatitis.
      ).

      Concluding remarks

      The past two decades of intense research have transformed the itch field. Itch biology grew from a subtext of the pain field to an interdisciplinary and highly collaborative area of study. Entirely unknown itch-sensing receptors and neural circuits were discovered and, more importantly, reconciled with existing inflammatory skin processes. These advances, for the first time, not only yielded an explanation for the psychophysiological manifestations of intensely pruritic skin disorders but also actionable therapeutic targets to manage what is perhaps the most debilitating symptom of these disorders. However, there are still many unknowns left to reveal. New itch mediators and processes are discovered continually, and the processes behind neural‒immune and neural‒epidermal cross-modulation are finally beginning to decode. Itch is a quickly advancing field with ample openings for paradigm-shifting breakthroughs. The most exciting discoveries are still yet to come.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      The authors would like to thank Xingzhong Dong, Lian Han, Brian Kim, and Michael Panneton for their thoughtful critiques of this paper. Their invaluable feedback greatly improved the quality of this manuscript.

      Author Contributions

      Visualization: CJG, NSG; Supervision: QL; Writing - Original Draft Preparation: CJG, NSG; Writing - Review and Editing: CJG, NSG, QL

      References

        • Ahern K.
        • Gilmore E.S.
        • Poligone B.
        Pruritus in cutaneous T-cell lymphoma: a review.
        J Am Acad Dermatol. 2012; 67: 760-768
        • Akira S.
        • Uematsu S.
        • Takeuchi O.
        Pathogen recognition and innate immunity.
        Cell. 2006; 124: 783-801
        • Akiyama T.
        • Lerner E.A.
        • Carstens E.
        Protease-activated receptors and itch.
        Handb Exp Pharmacol. 2015; 226: 219-235
        • Akiyama T.
        • Merrill A.W.
        • Zanotto K.
        • Carstens M.I.
        • Carstens E.
        Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice.
        J Pharmacol Exp Ther. 2009; 329: 945-951
        • Alemi F.
        • Kwon E.
        • Poole D.P.
        • Lieu T.
        • Lyo V.
        • Cattaruzza F.
        • et al.
        The TGR5 receptor mediates bile acid-induced itch and analgesia.
        J Clin Invest. 2013; 123: 1513-1530
        • Babina M.
        The pseudo-allergic/neurogenic route of mast cell activation via MRGPRX2: discovery, functional programs, regulation, relevance to disease, and relation with allergic stimulation.
        Itch. 2020; 5: e32
        • Beck L.A.
        • Thaçi D.
        • Hamilton J.D.
        • Graham N.M.
        • Bieber T.
        • Rocklin R.
        • et al.
        Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.
        N Engl J Med. 2014; 371: 130-139
        • Bickford R.G.
        Experiments relating to the itch sensation, its peripheral mechanism, and central pathways.
        Clin Sci. 1938; 3: 377-386
        • Böhm S.K.
        • Khitin L.M.
        • Grady E.F.
        • Aponte G.
        • Payan D.G.
        • Bunnett N.W.
        Mechanisms of desensitization and resensitization of proteinase-activated receptor-2.
        J Biol Chem. 1996; 271: 22003-22016
        • Brandt E.
        • Sivaprasad U.
        Th2 cytokines and atopic dermatitis.
        J Clin Cell Immunol. 2011; 2: 110
        • Brestoff J.R.
        • Kim B.S.
        • Saenz S.A.
        • Stine R.R.
        • Monticelli L.A.
        • Sonnenberg G.F.
        • et al.
        Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.
        Nature. 2015; 519: 242-246
        • Cavanaugh D.J.
        • Lee H.
        • Lo L.
        • Shields S.D.
        • Zylka M.J.
        • Basbaum A.I.
        • et al.
        Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli [published correction appears in Proc Natl Acad Sci USA 2009;106:11424].
        Proc Natl Acad Sci USA. 2009; 106: 9075-9080
        • Cedeno-Laurent F.
        • Singer E.M.
        • Wysocka M.
        • Benoit B.M.
        • Vittorio C.C.
        • Kim E.J.
        • et al.
        Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities.
        Clin Immunol. 2015; 158: 1-7
        • Chen Y.
        • Wang Z.L.
        • Yeo M.
        • Zhang Q.J.
        • López-Romero A.E.
        • Ding H.P.
        • et al.
        Epithelia-sensory neuron cross talk underlies cholestatic itch induced by lysophosphatidylcholine.
        Gastroenterology. 2021; 161: 301-317.e16
        • Chiu I.M.
        • Barrett L.B.
        • Williams E.K.
        • Strochlic D.E.
        • Lee S.
        • Weyer A.D.
        • et al.
        Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity [published correction appears in Elife 2015;4:e06720].
        Elife. 2014; 3: e04660
        • Diebold S.S.
        Recognition of viral single-stranded RNA by toll-like receptors.
        Adv Drug Deliv Rev. 2008; 60: 813-823
        • Dimitriadou V.
        • Rouleau A.
        • Dam Trung Tuong M.
        • Newlands G.J.F.
        • Miller H.R.P.
        • Luffau G.
        • et al.
        Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen.
        Clin Sci (Lond). 1994; 87: 151-163
        • Diogenes A.
        • Ferraz C.C.
        • Akopian A.N.
        • Henry M.A.
        • Hargreaves K.M.
        LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons.
        J Dent Res. 2011; 90: 759-764
        • Dong X.
        • Han S.
        • Zylka M.J.
        • Simon M.I.
        • Anderson D.J.
        A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons.
        Cell. 2001; 106: 619-632
        • Dong X.
        • Dong X.
        Peripheral and central mechanisms of itch.
        Neuron. 2018; 98: 482-494
        • Duan B.
        • Cheng L.
        • Ma Q.
        Spinal circuits transmitting mechanical pain and itch.
        Neurosci Bull. 2018; 34: 186-193
        • Dunford P.J.
        • O’Donnell N.
        • Riley J.P.
        • Williams K.N.
        • Karlsson L.
        • Thurmond R.L.
        The histamine H 4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells.
        J Immunol. 2006; 176: 7062-7070
        • Dussor G.
        • Zylka M.J.
        • Anderson D.J.
        • McCleskey E.W.
        Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors.
        J Neurophysiol. 2008; 99: 1581-1589
        • El-Zayat S.R.
        • Sibaii H.
        • Mannaa F.A.
        Toll-like receptors activation, signaling, and targeting: an overview.
        Bull Natl Res Cent. 2019; 43: 187
        • Emery E.C.
        • Ernfors P.
        Dorsal root ganglion neuron types and their functional specialization.
        in: The Oxford handbook of the neurobiology of pain. Oxford University Press, Oxford, United Kingdom2020: 127-155
        • Feng J.
        • Luo J.
        • Yang P.
        • Du J.
        • Kim B.S.
        • Hu H.
        Piezo2 channel–Merkel cell signaling modulates the conversion of touch to itch.
        Science. 2018; 360: 530-533
        • Flegel C.
        • Schöbel N.
        • Altmüller J.
        • Becker C.
        • Tannapfel A.
        • Hatt H.
        • et al.
        RNA-seq analysis of human trigeminal and dorsal root ganglia with a focus on chemoreceptors.
        PLoS One. 2015; 6e0128951
        • Forsythe P.
        Mast cells in neuroimmune interactions.
        Trends Neurosci. 2019; 42: 43-55
        • Grimes J.
        • Desai S.
        • Charter N.W.
        • Lodge J.
        • Moita Santos R.
        • Isidro-Llobet A.
        • et al.
        MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo-allergic and anaphylactoid reactions.
        Pharmacol Res Perspect. 2019; 6: e00547
        • Guo C.J.
        • Mack M.R.
        • Oetjen L.K.
        • Trier A.M.
        • Council M.L.
        • Pavel A.B.
        • et al.
        Kallikrein 7 promotes atopic dermatitis-associated itch independently of skin inflammation.
        J Invest Dermatol. 2020; 140: 1244-1252.e4
        • Guttman-Yassky E.
        • Silverberg J.I.
        • Nemoto O.
        • Forman S.B.
        • Wilke A.
        • Prescilla R.
        • et al.
        Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.
        J Am Acad Dermatol. 2019; 80: 913-921.e9
        • Gutzmer R.
        • Diestel C.
        • Mommert S.
        • Köther B.
        • Stark H.
        • Wittmann M.
        • et al.
        Histamine H4 receptor stimulation suppresses IL-12p70 production and mediates chemotaxis in human monocyte-derived dendritic cells.
        J Immunol. 2005; 174: 5224-5232
        • Han L.
        • Dong X.
        Itch mechanisms and circuits.
        Annu Rev Biophys. 2014; 43: 331-355
        • Han L.
        • Ma C.
        • Liu Q.
        • Weng H.J.
        • Cui Y.
        • Tang Z.
        • et al.
        A subpopulation of nociceptors specifically linked to itch.
        Nat Neurosci. 2013; 16: 174-182
        • Han Q.
        • Liu D.
        • Convertino M.
        • Wang Z.
        • Jiang C.
        • Kim Y.H.
        • et al.
        miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus.
        Neuron. 2018; 99: 449-463.e6
        • Han S.K.
        • Mancino V.
        • Simon M.I.
        Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons.
        Neuron. 2006; 52: 691-703
        • Hennino A.
        • Bérard F.
        • Guillot I.
        • Saad N.
        • Rozières A.
        • Nicolas J.F.
        Pathophysiology of urticaria.
        Clin Rev Allergy Immunol. 2006; 30: 3-11
        • Hill S.J.
        • Ganellin C.R.
        • Timmerman H.
        • Schwartz J.C.
        • Shankley N.P.
        • Young J.M.
        • et al.
        International Union of Pharmacology. XIII. Classification of histamine receptors.
        Pharmacol Rev. 1997; 49: 253-278
        • Hofstra C.L.
        • Desai P.J.
        • Thurmond R.L.
        • Fung-Leung W.P.
        Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells.
        J Pharmacol Exp Ther. 2003; 305: 1212-1221
        • Huang C.C.
        • Kim Y.S.
        • Olson W.P.
        • Li F.
        • Guo C.
        • Luo W.
        • et al.
        A histamine-independent itch pathway is required for allergic ocular itch.
        J Allergy Clin Immunol. 2016; 137: 1267-1270.e6
        • Huang C.C.
        • Yang W.
        • Guo C.
        • Jiang H.
        • Li F.
        • Xiao M.
        • et al.
        Anatomical and functional dichotomy of ocular itch and pain.
        Nat Med. 2018; 24: 1268-1276
        • Huang C.H.
        • Kuo I.C.
        • Xu H.
        • Lee Y.S.
        • Chua K.Y.
        Mite allergen induces allergic dermatitis with concomitant neurogenic inflammation in mouse.
        J Invest Dermatol. 2003; 121: 289-293
        • Huang J.
        • Polgár E.
        • Solinski H.J.
        • Mishra S.K.
        • Tseng P.Y.
        • Iwagaki N.
        • et al.
        Circuit dissection of the role of somatostatin in itch and pain [published correction appears in Nat Neurosci 2018;21:894].
        Nat Neurosci. 2018; 21: 707-716
        • Inagaki N.
        • Nakamura N.
        • Nagao M.
        • Musoh K.
        • Kawasaki H.
        • Nagai H.
        Participation of histamine H1 and H2 receptors in passive cutaneous anaphylaxis-induced scratching behavior in ICR mice.
        Eur J Pharmacol. 1999; 367: 361-371
        • Jariwala S.P.
        • Abrams E.
        • Benson A.
        • Fodeman J.
        • Zheng T.
        The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis.
        Clin Exp Allergy. 2011; 41: 1515-1520
        • Jaworecka K.
        • Muda-Urban J.
        • Rzepko M.
        • Reich A.
        Molecular aspects of pruritus pathogenesis in psoriasis.
        Int J Mol Sci. 2021; 22: 858
        • Jutel M.
        • Watanabe T.
        • Klunker S.
        • Akdis M.
        • Thomet O.A.
        • Malolepszy J.
        • et al.
        Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors.
        Nature. 2001; 413: 420-425
        • Kapur S.
        • Watson W.
        • Carr S.
        Atopic dermatitis.
        Allergy Asthma Clin Immunol. 2018; 14: 52
        • Kempkes C.
        • Buddenkotte J.
        • Cevikbas F.
        • Buhl T.
        • Steinhoff M.
        • Carstens E.
        • et al.
        Role of PAR-2 in Neuroimmune Communication and Itch.
        in: Carstens E. Akiyama T. Itch: mechanisms and treatment. CRC Press/Taylor & Francis, Boca Raton, FL2014: 215-234
        • Kim B.S.
        • Howell M.D.
        • Sun K.
        • Papp K.
        • Nasir A.
        • Kuligowski M.E.
        • et al.
        Treatment of atopic dermatitis with Ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream.
        J Allergy Clin Immunol. 2020; 145: 572-582
        • Kim B.S.
        • Siracusa M.C.
        • Saenz S.A.
        • Noti M.
        • Monticelli L.A.
        • Sonnenberg G.F.
        • et al.
        TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation.
        Sci Transl Med. 2013; 5: 170ra16
        • Kleij H.P.
        • Bienenstock J.
        Significance of conversation between mast cells and nerves.
        Allergy Asthma Clin Immunol Springer Nat. 2005; 1: 65-80
        • Komiya E.
        • Tominaga M.
        • Kamata Y.
        • Suga Y.
        • Takamori K.
        Molecular and cellular mechanisms of itch in psoriasis.
        Int J Mol Sci. 2020; 21: 8406
        • Kouzaki H.
        • O’Grady S.M.
        • Lawrence C.B.
        • Kita H.
        Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2.
        J Immunol. 2009; 183: 1427-1434
        • Li C.
        • Wang S.
        • Chen Y.
        • Zhang X.
        Somatosensory neuron typing with high-coverage single-cell RNA sequencing and functional analysis.
        Neurosci Bull. 2018; 34: 200-207
        • Li X.
        • Yang H.
        • Han Y.
        • Yin S.
        • Shen B.
        • Wu Y.
        • et al.
        Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors.
        J Allergy Clin Immunol. 2021; 147: 2236-2248.e16
        • Liedtke W.
        • Friedman J.M.
        Abnormal osmotic regulation in trpv4–/– mice.
        Proc Natl Acad Sci USA. 2003; 100: 13698-13703
        • Liu B.
        • Tai Y.
        • Achanta S.
        • Kaelberer M.M.
        • Caceres A.I.
        • Shao X.
        • et al.
        IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy.
        Proc Natl Acad Sci USA. 2016; 113: E7572-E7579
        • Liu Q.
        • Sikand P.
        • Ma C.
        • Tang Z.
        • Han L.
        • Li Z.
        • et al.
        Mechanisms of itch evoked by β-alanine.
        J Neurosci. 2012; 32: 14532-14537
        • Liu Q.
        • Tang Z.
        • Surdenikova L.
        • Kim S.
        • Patel K.N.
        • Kim A.
        • et al.
        Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
        Cell. 2009; 139: 1353-1365
        • Liu Q.
        • Weng H.J.
        • Patel K.N.
        • Tang Z.
        • Bai H.
        • Steinhoff M.
        • et al.
        The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
        Sci Signal. 2011; 4: ra45
        • Liu T.
        • Berta T.
        • Xu Z.Z.
        • Park C.K.
        • Zhang L.
        • Lü N.
        • et al.
        TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice.
        J Clin Invest. 2012; 122: 2195-2207
        • Liu T.
        • Han Q.
        • Chen G.
        • Huang Y.
        • Zhao L.X.
        • Berta T.
        • et al.
        Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice.
        Pain. 2016; 157: 806-817
        • Liu T.
        • Xu Z.Z.
        • Park C.K.
        • Berta T.
        • Ji R.R.
        Toll-like receptor 7 mediates pruritus.
        Nat Neurosci. 2010; 13: 1460-1462
        • Luo J.
        • Feng J.
        • Yu G.
        • Yang P.
        • Mack M.R.
        • Du J.
        • et al.
        Transient receptor potential vanilloid 4–expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.
        J Allergy Clin Immunol. 2018; 141: 608-619.e7
        • McNeil B.D.
        • Pundir P.
        • Meeker S.
        • Han L.
        • Undem B.J.
        • Kulka M.
        • et al.
        Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
        Nature. 2015; 519: 237-241
        • Meixiong J.
        • Anderson M.
        • Limjunyawong N.
        • Sabbagh M.F.
        • Hu E.
        • Mack M.R.
        • et al.
        Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch.
        Immunity. 2019; 50: 1163-1171.e5
        • Meixiong J.
        • Basso L.
        • Dong X.
        • Gaudenzio N.
        Nociceptor–mast cell sensory clusters as regulators of skin homeostasis.
        Trends Neurosci. 2020; 43: 130-132
        • Meixiong J.
        • Dong X.
        Mas-related G protein–coupled receptors and the biology of itch sensation.
        Annu Rev Genet. 2017; 51: 103-121
        • Meixiong J.
        • Vasavda C.
        • Green D.
        • Zheng Q.
        • Qi L.
        • Kwatra S.G.
        • et al.
        Identification of a bilirubin receptor that may mediate a component of cholestatic itch.
        Elife. 2019; 8: e44116
        • Meixiong J.
        • Vasavda C.
        • Snyder S.H.
        • Dong X.
        MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus.
        Proc Natl Acad Sci USA. 2019; 116: 10525-10530
        • Meng J.
        • Li Y.
        • Fischer M.J.M.
        • Steinhoff M.
        • Chen W.
        • Wang J.
        Th2 modulation of transient receptor potential channels: an unmet therapeutic intervention for atopic dermatitis.
        Front Immunol. 2021; 12: 696784
        • Meyer N.
        • Paul C.
        • Misery L.
        Pruritus in cutaneous T-cell lymphomas: frequent, often severe and difficult to treat.
        Acta Derm Venereol. 2010; 90: 12-17
        • Misery L.
        Chapter 8: Pruritus in cutaneous T-cell lymphomas.
        in: Carstens E. Akiyama T. Itch: mechanisms and treatment. CRC Press/Taylor & Francis, Boca Raton, FL2014
        • Mishra S.K.
        • Wheeler J.J.
        • Pitake S.
        • Ding H.
        • Jiang C.
        • Fukuyama T.
        • et al.
        Periostin activation of integrin receptors on sensory neurons induces allergic itch.
        Cell Rep. 2020; 31: 107472
        • Miyamoto T.
        • Nojima H.
        • Shinkado T.
        • Nakahashi T.
        • Kuraishi Y.
        Itch-associated response induced by experimental dry skin in mice.
        Jpn J Pharmacol. 2002; 88: 285-292
        • Mollanazar N.K.
        • Smith P.K.
        • Yosipovitch G.
        Mediators of chronic pruritus in atopic dermatitis: getting the itch out?.
        Clin Rev Allergy Immunol. 2016; 51: 263-292
        • Moniaga C.S.
        • Jeong S.K.
        • Egawa G.
        • Nakajima S.
        • Hara-Chikuma M.
        • Jeon J.E.
        • et al.
        Protease activity enhances production of thymic stromal lymphopoietin and basophil accumulation in flaky tail mice.
        Am J Pathol. 2013; 182: 841-851
        • Morita T.
        • McClain S.P.
        • Batia L.M.
        • Pellegrino M.
        • Wilson S.R.
        • Kienzler M.A.
        • et al.
        HTR7 mediates serotonergic acute and chronic itch.
        Neuron. 2015; 87: 124-138
        • Mössner R.
        • Lesch K.P.
        Role of serotonin in the immune system and in neuroimmune interactions.
        Brain Behav Immun. 1998; 12: 249-271
        • Nakagawa H.
        • Nemoto O.
        • Igarashi A.
        • Nagata T.
        Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study.
        Br J Dermatol. 2018; 178: 424-432
        • Nattkemper L.A.
        • Martinez-Escala M.E.
        • Gelman A.B.
        • Singer E.M.
        • Rook A.H.
        • Guitart J.
        • et al.
        Cutaneous T-cell lymphoma and pruritus: the expression of IL-31 and its receptors in the skin.
        Acta Derm Venereol. 2016; 96: 894-898
        • Nattkemper L.A.
        • Tey H.L.
        • Valdes-Rodriguez R.
        • Lee H.
        • Mollanazar N.K.
        • Albornoz C.
        • et al.
        The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch.
        J Invest Dermatol. 2018; 138: 1311-1317
        • Oetjen L.K.
        • Mack M.R.
        • Feng J.
        • Whelan T.M.
        • Niu H.
        • Guo C.J.
        • et al.
        Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch.
        Cell. 2017; 171: 217-228.e13
        • Pan H.
        • Fatima M.
        • Li A.
        • Lee H.
        • Cai W.
        • Horwitz L.
        • et al.
        Identification of a spinal circuit for mechanical and persistent spontaneous itch.
        Neuron. 2019; 103: 1135-1149.e6
        • Pariser D.M.
        • Bagel J.
        • Lebwohl M.
        • Yosipovitch G.
        • Chien E.
        • Spellman M.C.
        Serlopitant for psoriatic pruritus: a phase 2 randomized, double-blind, placebo-controlled clinical trial.
        J Am Acad Dermatol. 2020; 82: 1314-1320
        • Patel K.N.
        • Dong X.
        Itch: Cells, molecules, and circuits.
        ACS Chem Neurosci. 2011; 2: 17-25
        • Qi J.
        • Buzas K.
        • Fan H.
        • Cohen J.I.
        • Wang K.
        • Mont E.
        • et al.
        Painful pathways induced by TLR stimulation of dorsal root ganglion neurons.
        J Immunol. 2011; 186: 6417-6426
        • Qu L.
        • Fan N.
        • Ma C.
        • Wang T.
        • Han L.
        • Fu K.
        • et al.
        Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain.
        Brain. 2014; 137: 1039-1050
        • Ray P.
        • Torck A.
        • Quigley L.
        • Wangzhou A.
        • Neiman M.
        • Rao C.
        • et al.
        Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research.
        Pain. 2018; 159: 1325-1345
        • Reddy V.B.
        • Iuga A.O.
        • Shimada S.G.
        • LaMotte R.H.
        • Lerner E.A.
        Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors.
        J Neurosci. 2008; 28: 4331-4335
        • Reddy V.B.
        • Lerner E.A.
        Plant cysteine proteases that evoke itch activate protease-activated receptors.
        Br J Dermatol. 2010; 163: 532-535
        • Reddy V.B.
        • Sun S.
        • Azimi E.
        • Elmariah S.B.
        • Dong X.
        • Lerner E.A.
        Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs.
        Nat Commun. 2015; 6: 7864
        • Rendon A.
        • Schäkel K.
        Psoriasis pathogenesis and treatment.
        Int J Mol Sci. 2019; 20: 1475
        • Rogoz K.
        • Aresh B.
        • Freitag F.B.
        • Pettersson H.
        • Magnúsdóttir E.I.
        • Larsson Ingwall L.
        • et al.
        Identification of a neuronal receptor controlling anaphylaxis.
        Cell Rep. 2016; 14: 370-379
        • Rossbach K.
        • Nassenstein C.
        • Gschwandtner M.
        • Schnell D.
        • Sander K.
        • Seifert R.
        • et al.
        Histamine H1, H 3 and H 4 receptors are involved in pruritus.
        Neuroscience. 2011; 190: 89-102
        • Sakai K.
        • Akiyama T.
        Disinhibition of touch-evoked itch in a mouse model of psoriasis.
        J Invest Dermatol. 2019; 139: 1407-1410
        • Sanjel B.
        • Maeng H.J.
        • Shim W.S.
        BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus.
        Sci Rep. 2019; 9: 10888
        • Saraceno R.
        • Kleyn C.E.
        • Terenghi G.
        • Griffiths C.E.
        The role of neuropeptides in psoriasis.
        Br J Dermatol. 2006; 155: 876-882
        • Schön M.P.
        • Manzke V.
        • Erpenbeck L.
        Animal models of psoriasis—highlights and drawbacks.
        J Allergy Clin Immunol. 2021; 147: 439-455
        • Schwörer H.
        • Hartmann H.
        • Ramadori G.
        Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron.
        Pain. 1995; 61: 33-37
        • Scuron M.D.
        • Fay B.L.
        • Connell A.J.
        • Peel M.T.
        • Smith P.A.
        Ruxolitinib cream has dual efficacy on pruritus and inflammation in experimental dermatitis.
        Front Immunol. 2021; 11: 620098
        • Serhan N.
        • Basso L.
        • Sibilano R.
        • Petitfils C.
        • Meixiong J.
        • Bonnart C.
        • et al.
        House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation.
        Nat Immunol. 2019; 20: 1435-1443
        • Shim W.S.
        • Tak M.H.
        • Lee M.H.
        • Kim M.
        • Kim M.
        • Koo J.Y.
        • et al.
        TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase.
        J Neurosci. 2007; 27: 2331-2337
        • Shinohara T.
        • Harada M.
        • Ogi K.
        • Maruyama M.
        • Fujii R.
        • Tanaka H.
        • et al.
        Identification of a G protein-coupled receptor specifically responsive to beta-alanine.
        J Biol Chem. 2004; 279: 23559-23564
        • Siiskonen H.
        • Harvima I.
        Mast cells and sensory nerves contribute to neurogenic inflammation and pruritus in chronic skin inflammation.
        Front Cell Neurosci. 2019; 13: 422
        • Silverberg J.I.
        • Yosipovitch G.
        • Simpson E.L.
        • Kim B.S.
        • Wu J.J.
        • Eckert L.
        • et al.
        Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS.
        J Am Acad Dermatol. 2020; 82: 1328-1336
        • Singer E.M.
        • Shin D.B.
        • Nattkemper L.A.
        • Benoit B.M.
        • Klein R.S.
        • Didigu C.A.
        • et al.
        IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus.
        J Invest Dermatol. 2013; 133: 2783-2785
        • Solinski H.J.
        • Kriegbaum M.C.
        • Tseng P.Y.
        • Earnest T.W.
        • Gu X.
        • Barik A.
        • et al.
        Nppb neurons are sensors of mast cell-induced itch.
        Cell Rep. 2019; 26: 3561-3573.e4
        • Ständer S.
        • Yosipovitch G.
        Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus.
        Br J Dermatol. 2019; 181: 932-938
        • Steinhoff M.
        • Neisius U.
        • Ikoma A.
        • Fartasch M.
        • Heyer G.
        • Skov P.S.
        • et al.
        Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.
        J Neurosci. 2003; 23: 6176-6180
        • Strakhova M.I.
        • Nikkel A.L.
        • Manelli A.M.
        • Hsieh G.C.
        • Esbenshade T.A.
        • Brioni J.D.
        • et al.
        Localization of histamine H4 receptors in the central nervous system of human and rat.
        Brain Res. 2009; 1250: 41-48
        • Sun Y.G.
        • Chen Z.F.
        A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
        Nature. 2007; 448: 700-703
        • Tatemoto K.
        • Nozaki Y.
        • Tsuda R.
        • Konno S.
        • Tomura K.
        • Furuno M.
        • et al.
        Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors.
        Biochem Biophys Res Commun. 2006; 349: 1322-1328
        • Thaçi D.
        • Simpson E.L.
        • Beck L.A.
        • Bieber T.
        • Blauvelt A.
        • Papp K.
        • et al.
        Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.
        Lancet. 2016; 387: 40-52
        • Timmerman H.
        • Leurs R.
        • Van Der Goot H.
        Histamine receptors and their ligands: mechanisms and applications.
        in: Stein J. Bennett D. Coen C. Dunbar R. Goodwin G. Husain M. The curated reference collection in neuroscience and biobehavioral psychology. Elsevier, Amsterdam, The Netherlands2016: 1149-1166
        • Tong Q.
        • Ye C.P.
        • McCrimmon R.J.
        • Dhillon H.
        • Choi B.
        • Kramer M.D.
        • et al.
        Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia.
        Cell Metab. 2007; 5: 383-393
        • Trier A.M.
        • Mack M.R.
        • Fredman A.
        • Tamari M.
        • Ver Heul A.M.
        • Zhao Y.
        • et al.
        IL-33 signaling in sensory neurons promotes dry skin itch [e-pub ahead of print].
        J Allergy Clin Immunol. 2021; (accessed October 8, 2021)https://doi.org/10.1016/j.jaci.2021.09.014
        • Usoskin D.
        • Furlan A.
        • Islam S.
        • Abdo H.
        • Lönnerberg P.
        • Lou D.
        • et al.
        Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.
        Nat Neurosci. 2015; 18: 145-153
        • Valtcheva M.V.
        • Copits B.A.
        • Davidson S.
        • Sheahan T.D.
        • Pullen M.Y.
        • McCall J.G.
        • et al.
        Surgical extraction of human dorsal root ganglia from organ donors and preparation of primary sensory neuron cultures.
        Nat Protoc. 2016; 11: 1877-1888
        • Vij A.
        • Duvic M.
        Prevalence and severity of pruritus in cutaneous T cell lymphoma.
        Int J Dermatol. 2012; 51: 930-934
        • Volpe E.
        • Pattarini L.
        • Martinez-Cingolani C.
        • Meller S.
        • Donnadieu M.H.
        • Bogiatzi S.I.
        • et al.
        Thymic stromal lymphopoietin links keratinocytes and dendritic cell–derived IL-23 in patients with psoriasis.
        J Allergy Clin Immunol. 2014; 134: 373-381
        • Wang F.
        • Kim B.S.
        Itch: a paradigm of neuroimmune crosstalk.
        Immunity. 2020; 52: 753-766
        • Wang F.
        • Trier A.M.
        • Li F.
        • Kim S.
        • Chen Z.
        • Chai J.N.
        • et al.
        A basophil-neuronal axis promotes itch.
        Cell. 2021; 184: 422-440.e17
        • Wang H.
        • Zylka M.J.
        Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons.
        J Neurosci. 2009; 29: 13202-13209
        • Ward L.
        • Wright E.
        • McMahon S.B.
        A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain.
        Pain. 1996; 64: 129-138
        • Weisshaar E.
        • Dunker N.
        • Röhl F.W.
        • Gollnick H.
        Antipruritic effects of two different 5-HT3 receptor antagonists and an antihistamine in haemodialysis patients.
        Exp Dermatol. 2004; 13: 298-304
        • Wilson S.R.
        • Thé L.
        • Batia L.M.
        • Beattie K.
        • Katibah G.E.
        • McClain S.P.
        • et al.
        The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
        Cell. 2013; 155: 285-295
        • Woolf C.J.
        • Ma Q.
        Nociceptors--noxious stimulus detectors.
        Neuron. 2007; 55: 353-364
        • Xu H.
        • Shi X.
        • Li X.
        • Zou J.
        • Zhou C.
        • Liu W.
        • et al.
        Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review.
        J Neuroinflammation. 2020; 17: 356
        • Yu H.
        • Zhao T.
        • Liu S.
        • Wu Q.
        • Johnson O.
        • Wu Z.
        • et al.
        MRGPRX4 is a bile acid receptor for human cholestatic itch.
        ELife. 2019; 8: e48431