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Interactions of the Neuro‒Immune‒Stromal Triad in Itch

  • Pang-Yen Tseng
    Affiliations
    Molecular Genetics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
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  • Mark A. Hoon
    Correspondence
    Correspondence: Mark A. Hoon, Molecular Genetics Section, National Institutes of Dental and Craniofacial Research, National Institute of Health, 35 Convent Drive, Bethesda, Maryland 20892, USA.
    Affiliations
    Molecular Genetics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
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Published:October 15, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.443
      This review focuses on recent advances in understanding the mechanisms involved in itch signaling in the skin and how these new findings fit into the wider picture of the expression of itch mediators and their receptors in the dermal layer. Because at present studies mostly concentrate on single cellular compartments (e.g., neural alone), we suggest that they may miss important interactions with other compartments. Therefore, to fully appreciate pruritus, we propose that studies should consider (e.g., using transcriptomic information) signal transmission within the entire neuro‒immune‒stromal triad.

      Abbreviations:

      AD (atopic dermatitis), DC (dendritic cell), KC (keratinocyte), NPPB (natriuretic polypeptide B), scRNA-seq (single-cell RNA sequencing), Th2 (T helper type 2)

      Itch-Specific Sensory Neurons

      For many years, itch sensation was considered to be a mild form of pain in a model where itch was posited to trigger a low-intensity activation of nociceptive sensory neurons, whereas pain was suggested to evoke strong activation, and central circuits interpret these intensity differences generating separate sensations (
      • Melzack R.
      • Wall P.D.
      Pain mechanisms: a new theory.
      ;
      • Ross S.E.
      Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease.
      ). However, with the identification and characterization of an itch-specific neurotransmitter, GRP and its receptor, GRPR (
      • Sun Y.G.
      • Chen Z.F.
      A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
      ;
      • Sun Y.G.
      • Zhao Z.Q.
      • Meng X.L.
      • Yin J.
      • Liu X.Y.
      • Chen Z.F.
      Cellular basis of itch sensation.
      ), another model become favored. This model postulated that there are separate or partially discrete receptor sensory neurons that activate separate pain and itch neural pathways. Functional studies in mice uncovered at least two cell populations tuned to detect pruritogens by virtue of the genes they express (
      • Han L.
      • Ma C.
      • Liu Q.
      • Weng H.J.
      • Cui Y.
      • Tang Z.
      • et al.
      A subpopulation of nociceptors specifically linked to itch.
      ;
      • Mishra S.K.
      • Hoon M.A.
      The cells and circuitry for itch responses in mice.
      ;
      • 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.
      ;
      • Xing Y.
      • Chen J.
      • Hilley H.
      • Steele H.
      • Yang J.
      • Han L.
      Molecular signature of pruriceptive MrgprA3+ neurons.
      ). One neural subtype selectively expresses natriuretic polypeptide B (NPPB), an itch-specific neuropeptide; the second subtype expresses selectively the itch receptor MRGPRA3 (
      • 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.
      • 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.
      ). Several single-cell RNA sequencing (scRNA-seq) studies confirmed these populations (
      • Li C.L.
      • Li K.C.
      • Wu D.
      • Chen Y.
      • Luo H.
      • Zhao J.R.
      • et al.
      Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity.
      ;
      • Nguyen M.Q.
      • Wu Y.
      • Bonilla L.S.
      • von Buchholtz L.J.
      • Ryba N.J.P.
      Diversity amongst trigeminal neurons revealed by high throughput single cell sequencing.
      ;
      • Sharma N.
      • Flaherty K.
      • Lezgiyeva K.
      • Wagner D.E.
      • Klein A.M.
      • Ginty D.D.
      The emergence of transcriptional identity in somatosensory neurons.
      ;
      • 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 1a). Importantly, when these cell classes are activated, scratching is triggered (
      • 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].
      ;
      • Sun S.
      • Xu Q.
      • Guo C.
      • Guan Y.
      • Liu Q.
      • Dong X.
      Leaky gate model: intensity-dependent coding of pain and itch in the spinal cord.
      ).
      Figure thumbnail gr1
      Figure 1Analysis of scRNA-seq for the neuro‒immune‒stromal triad. UMAP analyses of scRNA-seq of (a) 11,139 mouse DRG neurons (GSE139088) (
      • Sharma N.
      • Flaherty K.
      • Lezgiyeva K.
      • Wagner D.E.
      • Klein A.M.
      • Ginty D.D.
      The emergence of transcriptional identity in somatosensory neurons.
      ), (b) 31,087 dermal immune cells from patients with AD, and (c) 63,512 dermal stromal cells from patients with AD (https://developmentcellatlas.ncl.ac.uk/datasets/hca_skin_portal/) (
      • Reynolds G.
      • Vegh P.
      • Fletcher J.
      • Poyner E.F.M.
      • Stephenson E.
      • Goh I.
      • et al.
      Developmental cell programs are co-opted in inflammatory skin disease.
      ). This approach reduces transcriptomic information from each sequenced cell to a single point, with distances between points reflecting the heterogeneity of the data between cells and cells with similar expression profiles clustering; for example, itch neurons (circled) form individual clusters that are segregated from other neurons. Clusters are named on the basis of prominent genes that define functions or accepted classifications: MRGD (polymodal nociceptor), LTMR, C-fiber LTMRs, TRPM8 (cold receptors), peptidergic (expressing CGRP and substance P), NPPB and MRGA3 (pruriceptors), Th, Tc, Treg, NK, ILCs, Mig.DC, DCs, Inf.Mac, and Macs. (df) Indicated genes (https://www.uniprot.org/) are shown for (d) DRG, (e) immune cells, and (f) stromal cells. Color bars indicate scaled average gene expression levels within the clusters. Dot sizes indicate the fractions of cells in a population that express given genes. AD, atopic dermatitis; DC, dendritic cell; DRG, dorsal root ganglion; ILC, innate lymphoid cell; Inf.Mac, inflammatory macrophage; LTMR, low-threshold mechanoreceptor; Mac, macrophage; Mig.DC, migratory dendritic cell; NPPB, natriuretic polypeptide B; scRNA-seq, single-cell RNA sequencing; ILCs, innate lymphoid cells; Tc, cytotoxic T cells; Th, T helper cells; Treg, regulatory T cell; UMAP, Uniform Manifold Approximation and Projection.

      Dermal Immune and Stromal Cells

      Although sensory neurons are key to itch sensation, it is well-known that immune cells are also involved because they release pruritogens. To understand the underlying causation of chronic itch, it is critical to consider changes in cell profiles that occur during inflammation and reflect on which of these are relevant for pruritus. For this reason, we analyzed scRNA-seq data of dermal immune and stromal cells from human atopic dermatitis (AD) samples (
      • Reynolds G.
      • Vegh P.
      • Fletcher J.
      • Poyner E.F.M.
      • Stephenson E.
      • Goh I.
      • et al.
      Developmental cell programs are co-opted in inflammatory skin disease.
      ) (Figure 1b and c). On disruption of the dermal barrier, innate and adaptive immunity is stimulated, and these result in physical, chemical, and cellular responses that protect against potential pathogens (
      • Veiga-Fernandes H.
      • Mucida D.
      Neuro-immune interactions at barrier surfaces.
      ). Stromal cells affect repair after injury, and this remodeling of the skin may also lead to pruritus (
      • Xu J.
      • Zanvit P.
      • Hu L.
      • Tseng P.Y.
      • Liu N.
      • Wang F.
      • et al.
      The cytokine TGF-β induces interleukin-31 expression from dermal dendritic cells to activate sensory neurons and stimulate wound itching.
      ). Therefore, itch can be a consequence of collateral damage caused by a defense against pathogens, by tissue repair, as well as by direct stimulation of sensory neurons by pruritogens.

      Itch Mediators and Their Intercellular Activation of Receptors

      In this section, we examine the examples of mediator receptor interactions where transcriptomic data help to define potential under-acknowledged connections. Because of space restraints, we are unable to comprehensively mention all the interactions (
      • Wang F.
      • Kim B.S.
      Itch: a paradigm of neuroimmune crosstalk.
      ). Instead, we highlight instances that we hope provoke a view of pruritus from the vantage point of an interconnected network of dermal cell types being involved in the generation of itch. Because data for human sensory neurons are unavailable, our analysis is limited to data from mouse dorsal root ganglia. In addition, because single-cell sequencing may not reveal low expression transcripts and because we only analyzed human AD skin cells, some interactions may be missed (
      • Nguyen M.Q.
      • Wu Y.
      • Bonilla L.S.
      • von Buchholtz L.J.
      • Ryba N.J.P.
      Diversity amongst trigeminal neurons revealed by high throughput single cell sequencing.
      ). We would also like to recognize that transcriptional expression does not guarantee functional significance (e.g., pruriceptor genes not only need to be transcribed but must also be translated, processed, and appropriately localized (
      • Zheng C.L.
      • Kawane S.
      • Bottomly D.
      • Wilmot B.
      Analysis considerations for utilizing RNA-Seq to characterize the brain transcriptome.
      ).

      Mast Cells

      Release of agents from mast cells elicits pruritus by direct activation of itch neurons, and they express all the biosynthetic apparatus to achieve this (Figure 1e) (
      • Buhl T.
      • Ikoma A.
      • Kempkes C.
      • Cevikbas F.
      • Sulk M.
      • Buddenkotte J.
      • et al.
      Protease-activated receptor-2 regulates neuro-epidermal communication in atopic dermatitis.
      ;
      • 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.
      ;
      • 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.
      ;
      • Voisin T.
      • Perner C.
      • Messou M.A.
      • Shiers S.
      • Ualiyeva S.
      • Kanaoka Y.
      • et al.
      The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.
      ). These agents include histamine, serotonin, leukotrienes, and sphingosine-1-phosphate (
      • Stone K.D.
      • Prussin C.
      • Metcalfe D.D.
      IgE, mast cells, basophils, and eosinophils.
      ) (Figure 1e). NPPB and MRGPRA3 neurons predominantly express histamine receptor HRH1, and HRH2 is expressed exclusively by NPPB neurons (Figure 1d). Receptors for serotonin (HTR1A and HTR1F) and lipid mediators leukotriene (CYSLTR2) and sphingosine-1-phosphate (S1PR1) are also found in NPPB neurons (Figure 1d) (
      • 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.
      ;
      • Voisin T.
      • Perner C.
      • Messou M.A.
      • Shiers S.
      • Ualiyeva S.
      • Kanaoka Y.
      • et al.
      The CysLT2R receptor mediates leukotriene C4-driven acute and chronic itch.
      ), but the physiological relevance of serotonin receptors is unclear. In addition to stimulating neurons, histamine activates other stromal cells, especially endothelial cells, to increase vascular permeability (
      • Ashina K.
      • Tsubosaka Y.
      • Nakamura T.
      • Omori K.
      • Kobayashi K.
      • Hori M.
      • et al.
      Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo.
      ). This fits well with the psychophysical observation that intradermal injection of histamine causes pricking, stinging, and burning sensations as well as skin flare and wheal (
      • Sikand P.
      • Shimada S.G.
      • Green B.G.
      • LaMotte R.H.
      Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage.
      ). Together with other agents released from mast cells, which also activate multiple cell targets, this shows the complexity of interactions that occur when mast cells release granules (Figures 1d‒f and 2). Furthermore, additional cell classes, including basophils, release these same mediators to induce itch (
      • Wang F.
      • Trier A.M.
      • Li F.
      • Kim S.
      • Chen Z.
      • Chai J.N.
      • et al.
      A basophil-neuronal axis promotes itch.
      ).
      Figure thumbnail gr2
      Figure 2Interactions between neurons, immune cells, and stromal cells related to pruritus. Summary schematic of the major itch mediator and receptor interactions in the neuro‒immune‒stromal triad. NPPB, natriuretic polypeptide B.
      Scientific illustration services provided by KatieRisVicari.com.

      Lymphoid Cells

      Cytokines are another major class of secreted transmitters whose expression is elevated in inflammatory skin disease (
      • Wang F.
      • Kim B.S.
      Itch: a paradigm of neuroimmune crosstalk.
      ). Historically, cytokines were thought to be released from immune and stromal cells regulating the recruitment, maturation, growth, and responsiveness of these populations. Perhaps because of this focus, their effect on neurons was overlooked for many years. scRNA-seq data reveal that sensory neurons express a restricted set of abundantly expressed cytokine receptors (Figure 1d). These patterns of expression agree with findings showing that IL-4 and IL-13 potentiate itch responses in mice (
      • Campion M.
      • Smith L.
      • Gatault S.
      • Métais C.
      • Buddenkotte J.
      • Steinhoff M.
      Interleukin-4 and interleukin-13 evoke scratching behaviour 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.
      ). The source of IL-31 and IL-13 is predominantly T cells (
      • Cevikbas F.
      • Wang X.
      • Akiyama T.
      • Kempkes C.
      • Savinko T.
      • Antal A.
      • et al.
      A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1.
      ;
      • Dillon S.R.
      • Sprecher C.
      • Hammond A.
      • Bilsborough J.
      • Rosenfeld-Franklin M.
      • Presnell S.R.
      • et al.
      Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice [published correction appears in Nat Immunol 2005;6:114].
      ;
      • Veiga-Fernandes H.
      • Mucida D.
      Neuro-immune interactions at barrier surfaces.
      ), and IL-4 is initially released from mast cells, eosinophils, and basophils, but then, by positive feedback, it is released by T helper type 2 (Th2) cells (
      • Gieseck 3rd, R.L.
      • Wilson M.S.
      • Wynn T.A.
      Type 2 immunity in tissue repair and fibrosis.
      ). In addition, certain classes of innate lymphoid cells are elevated in inflamed skin diseases, and the cytokines they produce may have effects on pruritus (
      • Bielecki P.
      • Riesenfeld S.J.
      • Hütter J.C.
      • Torlai Triglia E.
      • Kowalczyk M.S.
      • Ricardo-Gonzalez R.R.
      • et al.
      Skin-resident innate lymphoid cells converge on a pathogenic effector state.
      ;
      • 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.
      ;
      • van der Ploeg E.K.
      • Hermans M.A.W.
      • van der Velden V.H.J.
      • Dik W.A.
      • van Daele P.L.A.
      • Stadhouders R.
      Increased group 2 innate lymphoid cells in peripheral blood of adults with mastocytosis.
      ). Overexpression of IL-13 is most prominent in AD (
      • Tsoi L.C.
      • Rodriguez E.
      • Degenhardt F.
      • Baurecht H.
      • Wehkamp U.
      • Volks N.
      • et al.
      Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis.
      ), with other inflammatory skin diseases showing elevated expression of different combinations of cytokines (
      • Nograles K.E.
      • Davidovici B.
      • Krueger J.G.
      New insights in the immunologic basis of psoriasis.
      ). Notably, during injection, cytokines elicit direct albeit delayed mild scratch responses in mice, implicating them as potentiators of itch (
      • Campion M.
      • Smith L.
      • Gatault S.
      • Métais C.
      • Buddenkotte J.
      • Steinhoff M.
      Interleukin-4 and interleukin-13 evoke scratching behaviour in mice.
      ). Murine and human itch neurons express IL-31RA, and mouse itch neurons express IL-4RA and IL-13RA (
      • 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].
      ;
      • 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.
      ;
      • Solinski H.J.
      • Dranchak P.
      • Oliphant E.
      • Gu X.
      • Earnest T.W.
      • Braisted J.
      • et al.
      Inhibition of natriuretic peptide receptor 1 reduces itch in mice.
      ). With the exception of IL-31RA, which is selectively expressed in a specific population of NPPB neurons but in no other neurons (Figure 1d and f), receptors for these cytokines are expressed broadly in several classes of immune cells, consistent with their role in promoting Th2 inflammation. In addition, stromal cells express IL-4RA and IL-13RA, pointing to IL-4 and IL-13 acting in all dermal cellular compartments. Furthermore, because IL-4RA and IL-13RA are expressed in many classes of nociceptors, these cytokines are likely also involved in pain (
      • 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.
      ).

      Stromal Cells

      Stromal cells of the skin, such as keratinocytes (KCs), endothelial cells, pericytes, and fibroblasts, are not passive bystanders during inflammation producing bioactive peptides involved in itch and expressing receptors to several classes of mediators (Figure 1f). Several substances produced by stromal cells are reported to elicit itch reactions, including IL-33, TSLP, and endothelin (
      • Imai Y.
      Interleukin-33 in atopic dermatitis.
      ). Although Il-33 and endothelin are prominently released by endothelial cells, they are also reported to be secreted by immune cells (
      • Imai Y.
      Interleukin-33 in atopic dermatitis.
      ) and are expressed by KCs. IL-33 belongs to the IL-1 superfamily of cytokines and potently induces Th2 inflammation. Its receptor, IL-1RL1, together with IL-1RAP are coupled to the production of type 2 cytokines in polarized Th2 cells. Therefore, a major effect of IL-33 occurs through the activation of immune cells and the consequent release of pruritogens. In addition, IL-33 likely acts on KCs (Figure 1f). Similar to IL-33, TSLP, expressed by KCs, activates immune cells, and there is an abundant expression of its heteromeric receptors, CRLF2 and IL7R, in this cell compartment. Notably, TSLP activates mast cells, monocytes, dendritic cells (DCs), and Langerhans cells; therefore it has pleiotropic effects on the immune system and is part of the long-term changes in inflamed skin (
      • Han H.
      • Roan F.
      • Ziegler S.F.
      The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines.
      ;
      • Liu B.
      • Tai Y.
      • Liu B.
      • Caceres A.I.
      • Yin C.
      • Jordt S.E.
      Transcriptome profiling reveals Th2 bias and identifies endogenous itch mediators in poison ivy contact dermatitis.
      ). In addition, IL-33 and TSLP have been shown to directly stimulate sensory neurons (
      • 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.
      ;
      • 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.
      ). In contrast to IL-33 and TSLP, endothelin acts mainly on pericytes and fibroblasts through its receptors, EDNRA and EDNRB, which leads to vasoconstriction and tissue remodeling. In addition, both receptors are broadly expressed by several subtypes of sensory neurons, which are critical for endothelin-induced itch and nociception (
      • Magnúsdóttir E.I.
      • Grujic M.
      • Bergman J.
      • Pejler G.
      • Lagerström M.C.
      Mouse connective tissue mast cell proteases tryptase and carboxypeptidase A3 play protective roles in itch induced by endothelin-1.
      ).

      Sensory Neurons

      It has become apparent that sensory neurons not only detect pruritogens but can signal to dermal cells. The major peptides released are CGRPs (CALCA and CALCB) and substance P (TAC1), which are expressed in a broad population of neurons encompassing many types of nociceptors (Figure 1f). Congruous with CGRP and substance P being potent vasodilators, their receptors, CALCRL and TACR1, are found in stromal cells, and neurogenic inflammation associated with injury is thought to be the result of these interactions (
      • Basbaum A.I.
      • Bautista D.M.
      • Scherrer G.
      • Julius D.
      Cellular and molecular mechanisms of pain.
      ). Of note, for pruritus, CGRP can activate multiple classes of immune cells (Figure 1e), activating DC (
      • Kashem S.W.
      • Riedl M.S.
      • Yao C.
      • Honda C.N.
      • Vulchanova L.
      • Kaplan D.H.
      Nociceptive sensory fibers drive interleukin-23 production from CD301b+ dermal dendritic cells and drive protective cutaneous immunity [published correction appears in Immunity 2015;43:830].
      ), promoting psoriasis (
      • Ostrowski S.M.
      • Belkadi A.
      • Loyd C.M.
      • Diaconu D.
      • Ward N.L.
      Cutaneous denervation of psoriasiform mouse skin improves acanthosis and inflammation in a sensory neuropeptide-dependent manner.
      ), and altering the balance of infiltrating immune cells (
      • Baral P.
      • Umans B.D.
      • Li L.
      • Wallrapp A.
      • Bist M.
      • Kirschbaum T.
      • et al.
      Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia [published correction appears in Nat Med 2018;24:1625–6].
      ;
      • Nagashima H.
      • Mahlakõiv T.
      • Shih H.Y.
      • Davis F.P.
      • Meylan F.
      • Huang Y.
      • et al.
      Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation.
      ;
      • Pinho-Ribeiro F.A.
      • Baddal B.
      • Haarsma R.
      • O'Seaghdha M.
      • Yang N.J.
      • Blake K.J.
      • et al.
      Blocking neuronal signaling to immune cells treats streptococcal invasive infection.
      ). Similar to CGRP, substance P activates multiple classes of immune cells through its canonical receptor, TACR1 (
      • Payan D.G.
      • Brewster D.R.
      • Goetzl E.J.
      Specific stimulation of human T lymphocytes by substance P.
      ). However, in addition to TACR1, substance P activates MRGPRX2 found on mast cells (
      • Azimi E.
      • Reddy V.B.
      • Pereira P.J.S.
      • Talbot S.
      • Woolf C.J.
      • Lerner E.A.
      Substance P activates Mas-related G protein-coupled receptors to induce itch.
      ;
      • 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.
      ) and MRGPRA1 in sensory neurons (
      • Azimi E.
      • Reddy V.B.
      • Shade K.C.
      • Anthony R.M.
      • Talbot S.
      • Pereira P.J.S.
      • et al.
      Dual action of neurokinin-1 antagonists on Mas-related GPCRs.
      ), and substance P can stimulate MRGPRA1 in DCs initiating Th2 responses (
      • Perner C.
      • Flayer C.H.
      • Zhu X.
      • Aderhold P.A.
      • Dewan Z.N.A.
      • Voisin T.
      • et al.
      Substance P release by sensory neurons triggers dendritic cell migration and initiates the type-2 immune response to allergens.
      ).

      Summary

      Skin is a barrier to the external environment, and when it is damaged, a variety of protective strategies are employed. First, skin harbors the detectors for a plethora of challenges, including the well-recognized responses of the immune system and sensory neurons (Figure 2). Second, it has an array of defense strategies to repel invaders with immune and stromal cells delivering innate and acquired immunity and the sensory nerve system evoking scratching and other behavioral reactions. We propose that researchers in the itch field should consider this interplay when trying to decipher the mechanisms underlying pruritus.

      Conflict of Interest

      MAH is a patent holder on a National Institutes of Health patent for the use of natriuretic polypeptide B antagonists in the treatment of pruritus. The remaining author states no conflict of interest.

      Acknowledgments

      This work was supported by the intramural research program of the National Institute of Dental and Craniofacial Research , National Institutes of Health (project ZIADE000721-21 to MAH).

      Author Contributions

      Conceptualization: PYT, MAH; Writing: PYT, MAH; Writing – Original Draft Preparation: PYT, MAH; Writing – Review and Editing: MAH

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