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The Return of the Mast Cell: New Roles in Neuroimmune Itch Biology

  • Fang Wang
    Affiliations
    Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, Missouri, USA

    Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Ting-Lin B. Yang
    Affiliations
    Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, Missouri, USA
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  • Brian S. Kim
    Correspondence
    Correspondence: Brian S. Kim, 660 South Euclid Avenue, Campus Box 8123, St. Louis, Missouri 63110.
    Affiliations
    Division of Dermatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, Missouri, USA

    Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
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Open ArchivePublished:April 02, 2020DOI:https://doi.org/10.1016/j.jid.2019.12.011
      The mast cell–nerve unit classically has represented a fundamental neuroimmune axis in the development of itch because of the traditional prominence of histamine as a pruritogen. However, it is appreciated increasingly that most chronic itch disorders are likely nonhistaminergic in nature, provoking the hypothesis that other novel effector itch mechanisms derived from mast cells are important. In this review, we present an overview of classical mast cell biology and put these concepts into the context of recent advances in our understanding of the regulation and function of the mast cell–nerve unit in itch biology.

      Abbreviations:

      48/80 (compound 48/80), AD (atopic dermatitis), LT (leukotriene), MC (mast cell), NP (neuropeptide), PG (prostaglandin), SP (substance P)

      Introduction

      Originally described by Paul Ehrlich over a century ago, mast cells (MCs) have been viewed as important effector cells in allergic inflammatory processes that underlie diseases such as anaphylaxis, asthma, food allergy, and urticaria. Arising from pluripotent progenitor cells of the bone marrow, MC precursors circulate in the blood and enter tissues where they receive specific signals to undergo maturation and are long-lived (
      • Galli S.J.
      • Nakae S.
      • Tsai M.
      Mast cells in the development of adaptive immune responses.
      ,
      • Pasparakis M.
      • Haase I.
      • Nestle F.O.
      Mechanisms regulating skin immunity and inflammation.
      ). Mature MCs are activated by the binding of allergens to IgE, which is attached to the cell surface via the high-affinity receptor FcεRI. Binding of antigen results in cross-linking of IgE on FcεRI, which then rapidly induces MC degranulation and the release of various preformed effector molecules (
      • Amin K.
      The role of mast cells in allergic inflammation.
      ). Although this is the most well-described mode of MC activation, there are new pathways emerging that confer unique effector mechanisms and physiology.
      MCs have been shown to reside in close proximity with neurons in multiple tissues including the bladder (
      • Letourneau R.
      • Pang X.
      • Sant G.R.
      • Theoharides T.C.
      Intragranular activation of bladder mast cells and their association with nerve processes in interstitial cystitis.
      ), gut (
      • Stead R.H.
      • Tomioka M.
      • Quinonez G.
      • Simon G.T.
      • Felten S.Y.
      • Bienenstock J.
      Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves.
      ), lung (
      • Undem B.J.
      • Riccio M.M.
      • Weinreich D.
      • Ellis J.L.
      • Myers A.C.
      Neurophysiology of mast cell-nerve interactions in the airways.
      ), and skin (
      • Egan C.L.
      • Viglione-Schneck M.J.
      • Walsh L.J.
      • Green B.
      • Trojanowski J.Q.
      • Whitaker-Menezes D.
      • et al.
      Characterization of unmyelinated axons uniting epidermal and dermal immune cells in primate and murine skin.
      ), provoking the hypothesis that a primary function of the MC-nerve unit is to regulate a variety of neuroimmune interactions. Indeed, many mediators released from MCs are classified as pruritogens. Although histaminergic itch elicited by MCs has been recognized as one of the most well-known physiologic processes, surprisingly, antihistamines notoriously have demonstrated poor efficacy for most chronic itch conditions. Thus, the clear role of MCs in many clinical itch disorders has yet to be defined. Additionally, the release of various factors from innervating neurons, like neuropeptides (NPs) such as substance P (SP) and vasoactive intestinal peptide, has been reported to modulate MC function (
      • Kulka M.
      • Sheen C.H.
      • Tancowny B.P.
      • Grammer L.C.
      • Schleimer R.P.
      Neuropeptides activate human mast cell degranulation and chemokine production.
      ), suggesting that previously unrecognized mechanisms of regulation and effector function may shed new light on the relevance of MCs to chronic itch.
      In this review, we will focus on recent advances in MC biology that may explain new mechanisms by which MCs are regulated to elicit itch via histamine-independent pathways and have previously unrecognized roles in clinical itch disorders. These developments will likely open new avenues to novel therapeutic approaches for chronic itch.

       Classical and emerging MC-derived pruritogens

       Biogenic amines

      Histamine is a classical pruritogen released from MCs (Figure 1) and acts on 4 distinct G protein-coupled receptors (H1R, H2R, H3R, and H4R). Although neurons can broadly express H1R, H3R, and H4R, only H1R has been clearly demonstrated to be expressed by pruriceptive dorsal root ganglion neurons in humans and mice, whereas H4R expression has been reported on the rat dorsal root ganglion (
      • Dimitriadou V.
      • Rouleau A.
      • Dam Trung Tuong M.
      • Newlands G.J.
      • Miller H.R.
      • 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.
      ,
      • 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.
      ,
      • 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.
      ). The binding of histamine to H1R triggers the opening of the nonspecific cation channel TRPV1 on sensory neurons, resulting in membrane depolarization, a subsequent action potential, and itch sensation. However, given that current antihistamines currently target H1R or H2R, the role of H4R in itch remains an open question. In vitro experiments demonstrate that TRPV1 is also involved in the histamine-H4R itch axis and that H4R contributes to itch in preclinical murine models (
      • Jian T.
      • Yang N.
      • Yang Y.
      • Zhu C.
      • Yuan X.
      • Yu G.
      • et al.
      TRPV1 and PLC participate in histamine H4 receptor-induced itch.
      ,
      • Mack M.R.
      • Kim B.S.
      The itch-scratch cycle: a neuroimmune perspective.
      ). Indeed, H4R antagonists are currently in development for conditions like atopic dermatitis (AD), and future studies will be required to fully determine the role of histamine in chronic itch.
      Figure thumbnail gr1
      Figure 1Various ligands and receptors known to stimulate the growth, migration, and/or activation of mast cells. c-Kit (mast/stem cell growth factor receptor, CD117), which mediates responses to SCF, is a key growth factor for the development of mast cells. IgE cross-linking of the high-affinity receptor FcεRI is the classical pathway leading to mast cell activation and degranulation. A recently identified receptor is Mrgprb2 (murine)/MRGPRX2 (human), which responds to cationic compounds, numerous drugs, and various NPs and HDPs. Other receptors include PAR-2, chemokine receptors (CCRs/CXCRs), complement receptors, ET-1R, FcγRII for IgG, TLRs for LPS or PGN, and ST2 for IL-33. Mast cell activation leads to the release of multiple mediators such as histamine, serotonin (5-hydroxytryptamine), LTs, PGs, tryptase, and cytokines. Figure created with Biorender. ET-1R, endothelin 1 receptor; HDP, host defense peptide; LPS, lipopolysaccharide; LT, leukotriene; NP, neuropeptide; PG, prostaglandin; PGN, peptidoglycan; SCF, stem cell factor; TLR, toll-like receptor.
      Although rodent MCs are described to be an important source of serotonin (5-hydroxytryptamine), release of serotonin from human MCs has been implicated in specific disease contexts such as mastocytosis (
      • Herr N.
      • Bode C.
      • Duerschmied D.
      The effects of serotonin in immune cells.
      ,
      • Kushnir-Sukhov N.M.
      • Brown J.M.
      • Wu Y.L.
      • Kirshenbaum A.
      • Metcalfe D.D.
      Human mast cells are capable of serotonin synthesis and release.
      ). Notwithstanding of this, serotonin is defined as a pruritogen because cutaneous injection with serotonin successfully elicits itch in healthy humans and mice (
      • Akiyama T.
      • Carstens M.I.
      • Carstens E.
      Facial injections of pruritogens and algogens excite partly overlapping populations of primary and second-order trigeminal neurons in mice.
      ,
      • Weisshaar E.
      • Ziethen B.
      • Gollnick H.
      Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch?.
      ). Indeed, serotonin signaling is not only associated with itchy skin disorders such as AD (
      • Huang J.
      • Li G.
      • Xiang J.
      • Yin D.
      • Chi R.
      Immunohistochemical study of serotonin in lesions of chronic eczema.
      ), allergic contact dermatitis (
      • Liu B.
      • Escalera J.
      • Balakrishna S.
      • Fan L.
      • Caceres A.I.
      • Robinson E.
      • et al.
      TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis.
      ,
      • Lundeberg L.
      • Liang Y.
      • Sundström E.
      • Nordlind K.
      • Verhofstad A.
      • Lidén S.
      • et al.
      Serotonin in human allergic contact dermatitis. An immunohistochemical and high-performance liquid chromatographic study.
      ), and psoriasis (
      • Nordlind K.
      • Thorslund K.
      • Lonne-Rahm S.
      • Mohabbati S.
      • Berki T.
      • Morales M.
      • et al.
      Expression of serotonergic receptors in psoriatic skin.
      ), but has also been linked to itch caused by systemic conditions like cholestasis, uremia, and morphine-induced pruritus (
      • Aly M.
      • Ibrahim A.
      • Farrag W.
      • Abdelsalam K.
      • Mohamed H.
      • Tawfik A.
      Pruritus after intrathecal morphine for cesarean delivery: incidence, severity and its relation to serum serotonin level.
      ,
      • Kerr P.G.
      • Argiles A.
      • Mion C.
      Whole blood serotonin levels are markedly elevated in patients on dialytic therapy.
      ,
      • 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.
      ). However, the precise and robust manner in which serotonin can be effectively manipulated to treat chronic itch disorders in patients remains to be shown.

       Lipid mediators

      Lipids are the major components of cell membranes. PLA2s are a group of enzymes required for the release of arachidonic acid and lysophosphatidic acid. More than 30 PLA2s are encoded in the mammalian system (
      • Murakami M.
      • Taketomi Y.
      Secreted phospholipase A2 and mast cells.
      ). A recent RNA-sequencing study has found that the group IV PLA2 family is significantly enriched in itchy skin lesions compared with nonpruritic and nonlesional skin in patients with either AD or 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.
      ). These data indicate that MC-derived lipid mediators are highly connected to itch mechanisms underlying inflammatory skin conditions.
      Prostaglandins (PGs) are arachidonic acid metabolites and are broadly involved in inflammatory processes. Among the subtypes of PGs, PGD2 and PGE2 are the most significantly implicated in itch (Figure 1). Intradermal injection of PGE2 in human subjects has been shown to elicit itch via enhancing histamine- and serotonin-induced itching (
      • Fjellner B.
      • Hägermark O.
      Pruritus in polycythemia vera - treatment with aspirin and possibility of platelet involvement.
      ,
      • Hägermark O.
      • Strandberg K.
      Pruritogenic activity of prostaglandin E2.
      ). However, intradermal injection of PGE2 does not induce itch behavior in mice (
      • Andoh T.
      • Kuraishi Y.
      Intradermal leukotriene B-4, but not prostaglandin E2, induces itch-associated responses in mice.
      ), and even surprisingly, a topical application of PGE2 significantly suppressed spontaneous scratching in NC/Nga mice with AD-like disease (
      • Arai I.
      • Takano N.
      • Hashimoto Y.
      • Futaki N.
      • Sugimoto M.
      • Takahashi N.
      • et al.
      Prostanoid DP1 receptor agonist inhibits the pruritic activity in NC/Nga mice with atopic dermatitis.
      ). Similar to PGE2, application of PGD2 or the potent PGD2 agonist BW245C to the ocular surface can elicit itching and mild burning sensations in human subjects when treating glaucoma (
      • Nakajima M.
      • Goh Y.
      • Azuma I.
      • Hayaishi O.
      Effects of prostaglandin D2 and its analogue, BW245C, on intraocular pressure in humans.
      ). In contrast, topical applications of PGD2 or TS-022, a DP1 receptor agonist, have shown suppressive effects on spontaneous scratching in NC/Nga mice (
      • Arai I.
      • Takaoka A.
      • Hashimoto Y.
      • Honma Y.
      • Koizumi C.
      • Futaki N.
      • et al.
      Effects of TS-022, a newly developed prostanoid DP1 receptor agonist, on experimental pruritus, cutaneous barrier disruptions and atopic dermatitis in mice.
      ,
      • Arai I.
      • Takano N.
      • Hashimoto Y.
      • Futaki N.
      • Sugimoto M.
      • Takahashi N.
      • et al.
      Prostanoid DP1 receptor agonist inhibits the pruritic activity in NC/Nga mice with atopic dermatitis.
      ). Clinically, MC activation syndrome is a newly recognized collection of disorders that typically involves multiorgan inflammation because of the release of MC mediators. Patients with MC activation syndrome can present with chronic and relapsing itch (
      • Petra A.I.
      • Panagiotidou S.
      • Stewart J.M.
      • Conti P.
      • Theoharides T.C.
      Spectrum of mast cell activation disorders.
      ). Indeed, nonsteroidal anti-inflammatory drugs that inhibit PG synthesis have been reported to be effective in MC activation syndrome–associated itch (
      • Kesterson K.
      • Nahmias Z.
      • Brestoff J.R.
      • Bodet N.D.
      • Kau A.
      • Kim B.S.
      Generalized pruritus relieved by NSAIDs in the setting of mast cell activation syndrome.
      ). However, future studies will be required to fully define the role of PGs in various chronic itch disorders.
      Generated from arachidonic acid via the 5-lipoxygenase pathway, leukotrienes (LTs) are divided into 2 classes, namely, the chemoattractant LTB4 and the cysteinyl LTs (LTC4, LTD4, and LTE4) (
      • Luster A.D.
      • Tager A.M.
      T-cell trafficking in asthma: lipid mediators grease the way.
      ). In mice, intradermal injections of LTB4 have been shown to induce scratching behavior (
      • Andoh T.
      • Kuraishi Y.
      Intradermal leukotriene B-4, but not prostaglandin E2, induces itch-associated responses in mice.
      ,
      • Fernandes E.S.
      • Vong C.T.
      • Quek S.
      • Cheong J.
      • Awal S.
      • Gentry C.
      • et al.
      Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B4-induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1.
      ). Additionally, TRPV1 or TRPA1 antagonists have been shown to inhibit itch behavior in this context, suggesting that LTB4 is a pruritogen (
      • Fernandes E.S.
      • Vong C.T.
      • Quek S.
      • Cheong J.
      • Awal S.
      • Gentry C.
      • et al.
      Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B4-induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1.
      ). In the eye, subconjunctival injections of LTB4 have been shown to provoke site-directed scratching, and application of the LTB4 receptor antagonist ONO-4057 inhibits ragweed pollen–associated ocular scratching in mice (
      • Andoh T.
      • Sakai K.
      • Urashima M.
      • Kitazawa K.
      • Honma A.
      • Kuraishi Y.
      Involvement of leukotriene B4 in itching in a mouse model of ocular allergy.
      ). However, the role of cysteinyl LTs as pruritogens remains controversial. Studies have shown that applications of different cysteinyl LTs (LTC4, LTD4, or LTE4) to the eye do not induce itch behavior in guinea pigs (
      • Woodward D.F.
      • Nieves A.L.
      • Spada C.S.
      • Williams L.S.
      • Tuckett R.P.
      Characterization of a behavioral-model for peripherally evoked itch suggests platelet-activating-factor as a potent pruritogen.
      ), and scratching does not increase in mice receiving intradermal injections of LTD4 (
      • Andoh T.
      • Katsube N.
      • Maruyama M.
      • Kuraishi Y.
      Involvement of leukotriene B(4) in substance P-induced itch-associated response in mice.
      ). Notwithstanding this, a recently published study has shown that intradermal injection of LTC4 causes robust itch behavior 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.
      ). Collectively, these studies indicate that the role of various LTs in mediating itch remains a complex area requiring further investigation.

       MC-associated cytokines: IL-4, IL-13, and IL-31

      Beyond classical pruritogens, specific cytokines are increasingly recognized for their ability to function as pruritogens. Indeed, a recent study demonstrated that the MC-associated type 2 cytokines IL-4 and IL-13 can directly stimulate peripheral sensory neurons in vitro. Further, conditional deletion of the gene for IL-4Rα, which mediates both IL-4 and IL-13 signaling, on sensory neurons resulted in attenuation of AD-like 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.
      ). However, whether type 2 cytokines derived specifically from MCs mediate itch in vivo and in what contexts remains to be fully defined.
      IL-31, first discovered in 2004 (
      • 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.
      ), belongs to the gp130/IL-6 cytokine family. It is the first cytokine to be defined as a pruritogen because of its ability to directly stimulate sensory neurons to evoke itch (
      • 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.
      ). Although originally identified to be derived mainly from T helper type 2 cells, increasing evidence suggests that MCs might be a source of IL-31. Indeed, IL-31 mRNA was detected in a human MC line activated by the epithelial cell–derived antimicrobial peptides human β-defensin and LL-37 (
      • Niyonsaba F.
      • Ushio H.
      • Hara M.
      • Yokoi H.
      • Tominaga M.
      • Takamori K.
      • et al.
      Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells.
      ). More recently, IL-33 has been shown to activate human MCs to evoke the release of IL-31 (
      • Petra A.I.
      • Tsilioni I.
      • Taracanova A.
      • Katsarou-Katsari A.
      • Theoharides T.C.
      Interleukin 33 and interleukin 4 regulate interleukin 31 gene expression and secretion from human laboratory of allergic diseases 2 mast cells stimulated by substance P and/or immunoglobulin E.
      ). Additionally, in a number of chronic itch disorders closely associated with MC dysfunction, including chronic spontaneous urticaria, mastocytosis, and myeloproliferative neoplasms, serum and plasma levels of IL-31 have been found to be elevated (
      • Hartmann K.
      • Wagner N.
      • Rabenhorst A.
      • Pflanz L.
      • Leja S.
      • Förster A.
      • et al.
      Serum IL-31 levels are increased in a subset of patients with mastocytosis and correlate with disease severity in adult patients.
      ,
      • Lin W.
      • Zhou Q.
      • Liu C.
      • Ying M.
      • Xu S.
      Increased plasma IL-17, IL-31, and IL-33 levels in chronic spontaneous urticaria.
      ,
      • Raap U.
      • Wieczorek D.
      • Gehring M.
      • Pauls I.
      • Ständer S.
      • Kapp A.
      • et al.
      Increased levels of serum IL-31 in chronic spontaneous urticaria.
      ). Thus, studying the exact role of MCs in modulating IL-31 expression and the therapeutic potential of disruption of IL-31/IL-31RA interactions for MC-related itch disorders remains an exciting area of investigation.

       Regulation of MCs by Mrgprb2/MRGPRX2

      Although classically activated by IgE-mediated FcεRI aggregation, MCs have been shown to respond to a variety of other stimuli including complement, chemokines, adenosine, nerve growth factor, SP, host defense peptides, and basic peptides (Figure 1) (
      • Metz M.
      • Siebenhaar F.
      • Maurer M.
      Mast cell functions in the innate skin immune system.
      ,
      • 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.
      ,
      • Subramanian H.
      • Gupta K.
      • Ali H.
      Roles of Mas-related G protein–coupled receptor X2 on mast cell– mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases.
      ,
      • 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.
      ). These diverse pathways of MC activation result in the release of a wide range of inflammatory mediators (
      • Tal M.
      • Liberman R.
      Local injection of nerve growth factor (NGF) triggers degranulation of mast cells in rat paw.
      ,
      • Thangam E.B.
      • Jemima E.A.
      • Singh H.
      • Baig M.S.
      • Khan M.
      • Mathias C.B.
      • et al.
      The role of histamine and histamine receptors in mast cell-mediated allergy and inflammation: the hunt for new therapeutic targets.
      ). However, the precise contribution of these different pathways has remained poorly understood.
      It has been well recognized since the 1950s that the compound 48/80 (48/80) is a rapid and potent activator of MCs (
      • Paton W.D.M.
      Compound 48 80: a potent histamine liberator.
      ). Indeed, intradermal injection of 48/80 has been used as a tool in both mice and humans to probe the mechanisms underlying MC-elicited itch (
      • Fjellner B.
      • Lindelöf B.
      • Wahlgren C.F.
      • Lengstam I.
      Influence of Grenz rays and psychological factors on experimental pruritus induced by histamine and compound 48/80.
      ,
      • Goldberg A.
      • Korzets Z.
      • Bernheim J.
      • Mekori Y.A.
      Cutaneous responses to histamine, compound 48/80, and codeine in patients with chronic renal failure.
      ). However, for decades, the mechanism by which MCs responded to 48/80 was elusive. In 2015, McNeil et al. discovered that Mrgrpb2 is a highly specific receptor for MCs and mediates 48/80-induced MC responses in vitro and pseudoanaphylactic responses in vivo in mice (
      • 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.
      ). The human ortholog MRGPRX2 is also present on human MCs. Beyond 48/80, many synthetic compounds, peptidomimetic drugs, and endogenous peptides and amines have demonstrated activity in stimulating Mrgrpb2/MRGPRX2. More recently, Staphylococcus δ-toxin as well as antimicrobial peptides have been shown to directly stimulate this pathway to evoke MC activation (
      • Azimi E.
      • Reddy V.B.
      • Lerner E.A.
      Brief communication: MRGPRX2, atopic dermatitis and red man syndrome.
      ,
      • Zhang L.
      • McNeil B.D.
      Beta-defensins are proinflammatory pruritogens that activate Mrgprs.
      ). We speculate that this highly conserved mechanism may underlie conditions such as contact urticaria, in which patients develop rapid urticarial reactions to classical haptens, but often independently of IgE, and much too rapid to be driven by a delayed type hypersensitivity reaction. In addition, MRGPRX2 also has high fold changes on the RNA level in itchy skin lesions biopsied from patients with AD or 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.
      ), which indicates its broad involvement in itch-related dermatoses.
      Furthermore,
      • Gaudenzio N.
      • Sibilano R.
      • Marichal T.
      • Starkl P.
      • Reber L.L.
      • Cenac N.
      • et al.
      Different activation signals induce distinct mast cell degranulation strategies.
      showed that different stimuli influence the dynamics and features of MC degranulation in distinct ways. Stimulation of MRGPRX2 and other G protein-coupled receptors (e.g., C3aR, C5aR, and endothelin-1R) resulted in the rapid release of smaller and uniformly sized granules from human MCs, whereas IgE-induced degranulation led to slower and sustained activation associated with the release of larger granules (
      • Gaudenzio N.
      • Sibilano R.
      • Marichal T.
      • Starkl P.
      • Reber L.L.
      • Cenac N.
      • et al.
      Different activation signals induce distinct mast cell degranulation strategies.
      ). Collectively, these findings provoked the hypothesis that Mrgprb2/MRGPRX2-mediated activation of MCs may elicit distinct processes from the classical IgE-histamine axis so closely attributed to the physiology of the MC-nerve functional unit.

       The MC-itch nerve unit: Beyond IgE and histamine

      Because of the early history of histamine being defined as a pruritogen (
      • Dale H.H.
      • Laidlaw P.P.
      The physiological action of beta-iminazolylethylamine.
      ), the MC-nerve unit has classically been viewed as the key neuroimmune interaction that mediates itch. Indeed, the discovery of numerous itch-specific pathways on neurons, including gastrin-releasing peptide receptor (
      • Sun Y.G.
      • Chen Z.F.
      A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
      ), Mrgpra3 (
      • 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.
      ), Nppb (
      • Mishra S.K.
      • Hoon M.A.
      The cells and circuitry for itch responses in mice.
      ), IL-31 (
      • 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.
      ), and thymic stromal lymphopoietin (
      • 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.
      ), employed various methods to prove that these pathways were nonhistaminergic and/or MC-independent. However, despite the prominence of MCs in the neuroimmune paradigm of itch, their precise contribution to various chronic itch disorders and the effector mechanisms employed by these cells to evoke itch have remained poorly understood.
      To directly and simply address the role of MCs in itch, Solinski et al. recently undertook an elegant approach whereby mice expressing Cre-recombinase expressed under MC-specific mast cell protease 5 were crossed to r26-LSL-hM3Dq mice. This approach allowed for targeted insertion of the artificial hM3Dq receptor into MCs, allowing for pharmacogenetic activation of MCs in a specific manner in response to clozapine-N-oxide. As hypothesized, clozapine-N-oxide–induced activation of MCs was sufficient to induce itch, and in vitro activation of MCs led to the release of a variety of mediators including LTC4, serotonin, and sphingosine-1-phosphate. Strikingly, these mediators stimulated Nppb+ neurons that in turn depended on the canonical gastrin-releasing peptide–spinal cord circuit to ultimately evoke 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.
      ).
      In terms of regulation of MCs in 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.
      demonstrated that activation of Mrgprb2 by the endogenous PAMP 9-20 resulted in itch that commenced independently of the IgE-histamine axis. Although PAMP is classically a vasoregulatory peptide released from the adrenal medulla, the authors found that it was highly expressed in keratinocytes from lesional skin of patients with allergic contact dermatitis in conjunction with MC enrichment in the dermis. These findings provoked the hypothesis that epithelial cell–derived PAMP–dermal MC interactions may elicit allergic contact dermatitis–associated itch. Indeed, allergic contact dermatitis itch across 3 different murine models demonstrated dependence on Mrgprb2. Strikingly, PAMP-mediated Mrgprb2 stimulation resulted in preferential release of tryptase and lower release of histamine and serotonin from MCs, which is a distinct pattern of sensory neuronal activation from IgE-elicited itch (Figure 2), indicating that differential pathways to MC activation result in distinct neuronal responses. However, in contrast to PAMP, 48/80 was found to induce the release of similar amounts of histamine as IgE-mediated 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.
      ,
      • Yao J.H.
      • Cui M.
      • Li M.T.
      • Liu Y.N.
      • He Q.H.
      • Xiao J.J.
      • et al.
      Angiopoietin1 inhibits mast cell activation and protects against anaphylaxis.
      ). Thus, it is possible that different ligands induce different effector functions on MCs even upon stimulation of the same Mrgprb2 receptor. Further, in humans, skin injection of PAMP was shown to be mitigated by coinjection with an antihistamine (
      • Hasbak P.
      • Eskesen K.
      • Lind H.
      • Holst J.
      • Edvinsson L.
      The vasorelaxant effect of adrenomedullin, proadrenomedullin N-terminal 20 peptide and amylin in human skin.
      ), demonstrating the complexity of how MC stimulation may result in itch responses.
      Figure thumbnail gr2
      Figure 2The IgE-mediated versus Mrgprb2-mediated itch axis. Classical activation of mast cells by IgE results in the release of the monoamines such as histamine and serotonin. Mrgprb2 (murine)/MRGPRX2 (human) can be activated by various cationic substances, such as PAMP 9-20, compound 48/80, drugs, NPs, and HDPs. Mrgprb2-mediated activation of mast cells elicits distinct mechanisms of itch from classical IgE stimulation, in which tryptase is a major mediator whereas others such as histamine and serotonin are also included. Figure created with Biorender. HDP, host defense peptide; NP, neuropeptide.
      In addition to pruritogens, MCs are also a source of other mediators that may contribute to neurite elongation or outgrowth of sensory neurons. Nerve growth factor is one such molecule. Sensory nerve density has been shown to be increased in itchy skin lesions in AD and psoriasis and accompanied by increased numbers of degranulated MCs (
      • Chang S.E.
      • Han S.S.
      • Jung H.J.
      • Choi J.H.
      Neuropeptides and their receptors in psoriatic skin in relation to pruritus.
      ,
      • Tominaga M.
      • Takamori K.
      Itch and nerve fibers with special reference to atopic dermatitis: therapeutic implications.
      ). Thus, nerve growth factor released by MCs may be an underlying mechanism of this phenomenon.

       Neurons promoting MC activation and neuroinflammation

      The primary afferent neurons responding to MC-derived mediators release NPs like calcitonin gene-related peptide, SP, and vasoactive intestinal peptide through calcium influx. Indeed, multiple prior studies have demonstrated that some NPs can directly stimulate MCs to evoke the release of various proinflammatory factors (Figure 1) (
      • Lee M.G.
      • Dong X.Z.
      • Liu Q.
      • Patel K.N.
      • Choi O.H.
      • Vonakis B.
      • et al.
      Agonists of the mas-related gene (Mrgs) orphan receptors as novel mediators of mast cell-sensory nerve interactions.
      ,
      • Manning B.M.
      • Gruba S.M.
      • Meyer A.F.
      • Haynes C.L.
      Neuropeptide-induced mast cell degranulation and characterization of signaling modulation in response to IgE conditioning.
      ,
      • Roosterman D.
      • Goerge T.
      • Schneider S.W.
      • Bunnett N.W.
      • Steinhoff M.
      Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.
      ,
      • Steinhoff M.
      • Vergnolle N.
      • Young S.H.
      • Tognetto M.
      • Amadesi S.
      • Ennes H.S.
      • et al.
      Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.
      ). Recent studies demonstrated that SP activates MCs via Mrgprb2 to evoke neurogenic inflammation and pain behavior (
      • Green D.P.
      • Limjunyawong N.
      • Gour N.
      • Pundir P.
      • Dong X.
      A mast-cell-specific receptor mediates neurogenic inflammation and pain.
      ,
      • 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.
      ). It is increasingly appreciated that MCs can be activated by NPs to promote neurogenic inflammation in a variety of contexts. However, how itch-sensory neurons are directly involved in this process is an exciting field of future investigation.
      A large proportion of primary afferent neurons express PAR-2, one of the known receptors for tryptase, whose activation promotes the release of calcitonin gene-related peptide and SP leading to neurogenic tissue inflammation and edema (
      • Roosterman D.
      • Goerge T.
      • Schneider S.W.
      • Bunnett N.W.
      • Steinhoff M.
      Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.
      ,
      • Steinhoff M.
      • Vergnolle N.
      • Young S.H.
      • Tognetto M.
      • Amadesi S.
      • Ennes H.S.
      • et al.
      Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.
      ). Other MC-derived itch mediators such as histamine also interact with their specific receptors on neurons to cause the release of NPs as well (
      • Gupta K.
      • Harvima I.T.
      Mast cell-neural interactions contribute to pain and itch.
      ,
      • Subramanian H.
      • Gupta K.
      • Ali H.
      Roles of Mas-related G protein–coupled receptor X2 on mast cell– mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases.
      ). Both SP and vasoactive intestinal peptide have been shown to activate murine and human MCs via Mrgprb2 and MRGPRX2, respectively (
      • Subramanian H.
      • Gupta K.
      • Ali H.
      Roles of Mas-related G protein–coupled receptor X2 on mast cell– mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases.
      ). Thus, in addition to the new insights into the MC-nerve unit as a key mediator of itch sensation, understanding how sensory neurons directly regulate MC function and tissue inflammation is also a major outstanding area of inquiry.
      It is well known that stress aggravates itch symptoms; however, the mechanisms remain poorly understood. Intriguingly, animal experiments have shown that both brain and skin MCs are activated in the setting of stress (
      • Esposito P.
      • Chandler N.
      • Kandere K.
      • Basu S.
      • Jacobson S.
      • Connolly R.
      • et al.
      Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress.
      ,
      • Singh L.K.
      • Pang X.Z.
      • Alexacos N.
      • Letourneau R.
      • Theoharides T.C.
      Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: A link to neurogenic skin disorders.
      ). Additionally, in patients with AD, stress increases allergen-induced skin wheal reactions and serum levels of SP, vasoactive intestinal peptide, and nerve growth factor (
      • Kimata H.
      Enhancement of allergic skin wheal responses in patients with atopic eczema/dermatitis syndrome by playing video games or by a frequently ringing mobile phone.
      ). Thus, MCs could be key mediators of the stress-itch axis and remain a major gap in understanding itch behavior.

       Summary and future directions

      Although the MC-nerve unit has classically represented a fundamental link in the neuroimmune itch circuit, its precise contribution to various chronic itch disorders has remained poorly defined. Based on new understanding, several major questions remain. What is the precise role of MCs in other chronic itch disorders like AD, chronic pruritus of unknown origin (
      • Xu A.Z.
      • Tripathi S.V.
      • Kau A.L.
      • Schaffer A.
      • Kim B.S.
      Immune dysregulation underlies a subset of patients with chronic idiopathic pruritus.
      ), and prurigo nodularis (
      • Zeidler C.
      • Tsianakas A.
      • Pereira M.
      • Ständer H.
      • Yosipovitch G.
      • Ständer S.
      Chronic prurigo of nodular type: a review.
      )? Can antagonists for various G protein-coupled receptors such as MRGPRX2 be employed to treat such chronic itch disorders, and which effector molecules are the most important therapeutic targets? Finally, given that MC stabilizers have poor efficacy in chronic itch disorders such as AD (
      • Benton E.C.
      • McFarlane H.A.
      • Barnetson R.S.
      Trial of nedocromil sodium in atopic eczema.
      ) and the striking similarity between MCs and basophils, do homologous mechanisms exist within their rare, circulating counterparts? Ever since their original discovery, MCs continue to unveil their complex and important role in neurosensory biology and beyond.

      ORCIDs

      Conflict of Interest

      Dr. Kim has served as a consultant for AbbVie, Cara Therapeutics, Concert Pharmaceuticals, Incyte Corporation, Menlo Therapeutics, and Pfizer. He has also participated on the advisory board for Cara Therapeutics, Celgene Corporation, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Sanofi, and Theravance Biopharma. He is also Founder, Chief Scientific Officer, and stockholder of Nuogen Pharma. He is stockholder of Locus Biosciences. All other authors state no conflicts of interest.

      Acknowledgments

      The authors thank all members in Kim lab for helpful comments and discussion. This work is supported by the Doris Duke Charitable Foundation , LEO Pharma , and the National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health [NIH ( K08AR065577 and R01AR070116 )].

      Author Contributions

      Conceptualization: FW, BSK; Data Curation: FW; Funding Acquisition: BSK; Methodology: FW, TBY, BSK; Resources: FW, TBY, BSK; Supervision: BSK; Validation: BSK; Visualization: FW, TBY, BSK; Writing - Original Draft Preparation: FW, BSK; Writing - Review and Editing: FW, BSK

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