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Role of Type I Cannabinoid Receptor in Sensory Neurons in Psoriasiform Skin Inflammation and Pruritus

  • Author Footnotes
    5 These authors contributed equally to this work.
    Xin Liu
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Author Footnotes
    5 These authors contributed equally to this work.
    Li Li
    Footnotes
    5 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, School of Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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  • Jian Jiang
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Wenqiang Ge
    Affiliations
    Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yuqiong Huang
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Zilin Jin
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • XinXin Liu
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Yi Kong
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Ouyang Zhanmu
    Affiliations
    Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Xin Zeng
    Affiliations
    Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, China
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  • Fei Li
    Affiliations
    Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, China
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  • Man Li
    Affiliations
    Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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  • Hongxiang Chen
    Correspondence
    Correspondence: Hongxiang Chen, Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Number 1277, Jiefang Avenue, Wuhan 430030, China.
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen, China
    Search for articles by this author
  • Author Footnotes
    5 These authors contributed equally to this work.
Published:November 18, 2022DOI:https://doi.org/10.1016/j.jid.2022.10.014
      Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and antipruritus effects against inflammation-based skin diseases, but the specific mechanism remains to be explored. In this study, we found that the activation of CB1R significantly relieved the scratching behavior and skin inflammation in a psoriatic mouse model, whereas CB1R antagonist aggravated these symptoms. Because the expression of CB1R was abundant in dorsal root ganglia, we constructed mice with conditional CB1R knockout in primary sensory neurons and found that imiquimod-induced psoriasiform inflammation and itch were both worsened in CB1R-conditional knockout mice. Next, we observed that the CB1R was mostly located in peptidergic neurons, and deletion of CB1R in primary sensory neurons promoted the production and release of substance P to the skin tissue. Furthermore, the elevated substance P in the skin affected the activation of extracellular signal‒regulated kinase in keratinocytes and induced the accumulation of mast cells in the dermis. Finally, we showed that blocking the substance P signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by imiquimod in CB1R-conditional knockout mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus by regulating substance P expression.

      Graphical abstract

      Abbreviations:

      BDNF (brain-derived neurotrophic factor), CB1R (type I cannabinoid receptor), CB1R-cKO (type I cannabinoid receptor‒conditional knockout), CBR (cannabinoid receptor), CGRP (calcitonin gene-related peptide), DRG (dorsal root ganglia), ERK (extracellular signal‒regulated kinase), IMQ (imiquimod), KCs (keratinocytes), MCs (mast cells), SP (substance P), WT (wild type)
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      References

        • Abraira V.E.
        • Ginty D.D.
        The sensory neurons of touch.
        Neuron. 2013; 79: 618-639
        • Alam M.
        • Buddenkotte J.
        • Ahmad F.
        • Steinhoff M.
        Neurokinin 1 receptor antagonists for pruritus.
        Drugs. 2021; 81: 621-634
        • Amatya B.
        • El-Nour H.
        • Holst M.
        • Theodorsson E.
        • Nordlind K.
        Expression of tachykinins and their receptors in plaque psoriasis with pruritus.
        Br J Dermatol. 2011; 164: 1023-1029
        • Avila C.
        • Massick S.
        • Kaffenberger B.H.
        • Kwatra S.G.
        • Bechtel M.
        Cannabinoids for the treatment of chronic pruritus: a review.
        J Am Acad Dermatol. 2020; 82: 1205-1212
        • 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.
        JCI Insight. 2016; 1e89362
        • Bandyopadhyay M.
        • Morelli A.E.
        • Balmert S.C.
        • Ward N.L.
        • Erdos G.
        • Sumpter T.L.
        • et al.
        Skin codelivery of contact sensitizers and neurokinin-1 receptor antagonists integrated in microneedle arrays suppresses allergic contact dermatitis.
        J Allergy Clin Immunol. 2022; 150: 114-130
        • Barry D.M.
        • Liu X.T.
        • Liu B.
        • Liu X.Y.
        • Gao F.
        • Zeng X.
        • et al.
        Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors.
        Nat Commun. 2020; 11: 1397
        • Bíró T.
        • Tóth B.I.
        • Haskó G.
        • Paus R.
        • Pacher P.
        The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities.
        Trends Pharmacol Sci. 2009; 30: 411-420
        • Brunoni A.R.
        • Lotufo P.A.
        • Sabbag C.
        • Goulart A.C.
        • Santos I.S.
        • Benseñor I.M.
        Decreased brain-derived neurotrophic factor plasma levels in psoriasis patients.
        Braz J Med Biol Res. 2015; 48: 711-714
        • 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
        • Cohen J.A.
        • Edwards T.N.
        • Liu A.W.
        • Hirai T.
        • Jones M.R.
        • Wu J.
        • et al.
        Cutaneous TRPV1+ neurons trigger protective innate Type 17 anticipatory immunity.
        Cell. 2019; 178: 919-932.e14
        • Davis M.P.
        Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands.
        Expert Opin Investig Drugs. 2014; 23: 1123-1140
        • Dvorak M.
        • Watkinson A.
        • McGlone F.
        • Rukwied R.
        Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin.
        Inflamm Res. 2003; 52: 238-245
        • Elewski B.
        • Alexis A.F.
        • Lebwohl M.
        • Stein Gold L.
        • Pariser D.
        • Del Rosso J.
        • et al.
        Itch: an under-recognized problem in psoriasis.
        J Eur Acad Dermatol Venereol. 2019; 33: 1465-1476
        • Farber E.M.
        • Lanigan S.W.
        • Boer J.
        The role of cutaneous sensory nerves in the maintenance of psoriasis.
        Int J Dermatol. 1990; 29: 418-420
        • Fukamachi S.
        • Mori T.
        • Sakabe J.
        • Shiraishi N.
        • Kuroda E.
        • Kobayashi M.
        • et al.
        Topical cholecystokinin depresses itch-associated scratching behavior in mice.
        J Invest Dermatol. 2011; 131: 956-961
        • Gaffal E.
        • Cron M.
        • Glodde N.
        • Bald T.
        • Kuner R.
        • Zimmer A.
        • et al.
        Cannabinoid 1 receptors in keratinocytes modulate proinflammatory chemokine secretion and attenuate contact allergic inflammation.
        J Immunol. 2013; 190: 4929-4936
        • Green D.P.
        • Limjunyawong N.
        • Gour N.
        • Pundir P.
        • Dong X.
        A mast-cell-specific receptor mediates neurogenic inflammation and pain.
        Neuron. 2019; 101: 412-420.e3
        • Guo J.
        • Qi C.
        • Liu Y.
        • Guo X.
        • Meng Y.
        • Zhao J.
        • et al.
        Terrestrosin D ameliorates skin lesions in an imiquimod-induced psoriasis-like murine model by inhibiting the interaction between substance P and dendritic cells.
        Phytomedicine. 2022; 95: 153864
        • Haruna T.
        • Soga M.
        • Morioka Y.
        • Hikita I.
        • Imura K.
        • Furue Y.
        • et al.
        S-777469, a novel cannabinoid type 2 receptor agonist, suppresses itch-associated scratching behavior in rodents through inhibition of itch signal transmission.
        Pharmacology. 2015; 95: 95-103
        • Joseph T.
        • Kurian J.
        • Warwick D.J.
        • Friedmann P.S.
        Unilateral remission of psoriasis following traumatic nerve palsy.
        Br J Dermatol. 2005; 152: 185-186
        • Kim H.J.
        • Kim B.
        • Park B.M.
        • Jeon J.E.
        • Lee S.H.
        • Mann S.
        • et al.
        Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model.
        Int J Dermatol. 2015; 54: e401-e408
        • Kim J.
        • Krueger J.G.
        Highly effective new treatments for psoriasis target the IL-23/Type 17 T cell autoimmune axis.
        Annu Rev Med. 2017; 68: 255-269
        • Lau J.
        • Minett M.S.
        • Zhao J.
        • Dennehy U.
        • Wang F.
        • Wood J.N.
        • et al.
        Temporal control of gene deletion in sensory ganglia using a tamoxifen-inducible Advillin-Cre-ERT2 recombinase mouse.
        Mol Pain. 2011; 7: 100
        • Lay M.
        • Dong X.
        Neural mechanisms of itch.
        Annu Rev Neurosci. 2020; 43: 187-205
        • Lee S.H.
        • Tonello R.
        • Choi Y.
        • Jung S.J.
        • Berta T.
        Sensory neuron-expressed TRPC4 is a target for the relief of psoriasiform itch and skin inflammation in mice.
        J Invest Dermatol. 2020; 140: 2221-2229.e6
        • Li L.
        • Liu X.
        • Ge W.
        • Chen C.
        • Huang Y.
        • Jin Z.
        • et al.
        CB2R deficiency exacerbates imiquimod-induced psoriasiform dermatitis and itch through the neuro-immune pathway.
        Front Pharmacol. 2022; 13: 790712
        • Liu J.Y.
        • Hu J.H.
        • Zhu Q.G.
        • Li F.Q.
        • Sun H.J.
        Substance P receptor expression in human skin keratinocytes and fibroblasts.
        Br J Dermatol. 2006; 155: 657-662
        • Liu Y.
        • Jia M.
        • Wu C.
        • Zhang H.
        • Chen C.
        • Ge W.
        • et al.
        Transcriptomic Profiling in Mice with CB1 receptor Deletion in Primary Sensory Neurons Suggests New analgesic Targets for Neuropathic Pain.
        Front Pharmacol. 2021; 12: 781237
        • Massa F.
        • Marsicano G.
        • Hermann H.
        • Cannich A.
        • Monory K.
        • Cravatt B.F.
        • et al.
        The endogenous cannabinoid system protects against colonic inflammation.
        J Clin Invest. 2004; 113: 1202-1209
        • 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
        • Misery L.
        • Brenaut E.
        • Pierre O.
        • Le Garrec R.
        • Gouin O.
        • Lebonvallet N.
        • et al.
        Chronic itch: emerging treatments following new research concepts.
        Br J Pharmacol. 2021; 178: 4775-4791
        • Morelli A.E.
        • Sumpter T.L.
        • Rojas-Canales D.M.
        • Bandyopadhyay M.
        • Chen Z.
        • Tkacheva O.
        • et al.
        Neurokinin-1 receptor signaling is required for efficient Ca2+ flux in T-cell-receptor-activated T cells.
        Cell Rep. 2020; 30 (3448-65.e8)
        • 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
        • 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.
        J Invest Dermatol. 2011; 131: 1530-1538
        • Pithadia D.J.
        • Reynolds K.A.
        • Lee E.B.
        • Wu J.J.
        Psoriasis-associated itch: etiology, assessment, impact, and management.
        J Dermatolog Treat. 2020; 31: 18-26
        • Qin B.
        • Sun C.
        • Chen L.
        • Wang S.
        • Yang J.
        • Xie Z.
        • et al.
        The nerve injuries attenuate the persistence of psoriatic lesions.
        J Dermatol Sci. 2021; 102: 85-93
        • Riol-Blanco L.
        • Ordovas-Montanes J.
        • Perro M.
        • Naval E.
        • Thiriot A.
        • Alvarez D.
        • et al.
        Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.
        Nature. 2014; 510: 157-161
        • 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
        • Sivesind T.E.
        • Maghfour J.
        • Rietcheck H.
        • Kamel K.
        • Malik A.S.
        • Dellavalle R.P.
        Cannabinoids for the treatment of dermatologic conditions.
        JID Innov. 2022; 2: 100095
        • Spradley J.M.
        • Davoodi A.
        • Gee L.B.
        • Carstens M.I.
        • Carstens E.
        Differences in peripheral endocannabinoid modulation of scratching behavior in facial vs. spinally-innervated skin.
        Neuropharmacology. 2012; 63: 743-749
        • 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
        • Sugawara K.
        • Zákány N.
        • Hundt T.
        • Emelianov V.
        • Tsuruta D.
        • Schäfer C.
        • et al.
        Cannabinoid receptor 1 controls human mucosal-type mast cell degranulation and maturation in situ.
        J Allergy Clin Immunol. 2013; 132: 182-193
        • Szepietowski J.C.
        • Reich A.
        Itch in psoriasis management.
        Curr Probl Dermatol. 2016; 50: 102-110
        • Visse K.
        • Blome C.
        • Phan N.Q.
        • Augustin M.
        • Ständer S.
        Efficacy of body lotion containing N-palmitoylethanolamine in subjects with chronic pruritus due to dry skin: a Dermatocosmetic study.
        Acta Derm Venereol. 2017; 97: 639-641
        • Wang W.
        • Wang H.
        • Zhao Z.
        • Huang X.
        • Xiong H.
        • Mei Z.
        Thymol activates TRPM8-mediated Ca2+ influx for its antipruritic effects and alleviates inflammatory response in imiquimod-induced mice.
        Toxicol Appl Pharmacol. 2020; 407: 115247
        • Wang Y.
        • Li P.
        • Zhang L.
        • Fu J.
        • Di T.
        • Li N.
        • et al.
        Stress aggravates and prolongs imiquimod-induced psoriasis-like epidermal hyperplasis and IL-1β/IL-23p40 production.
        J Leukoc Biol. 2020; 108: 267-281
        • Yamamoto Y.
        • Otsuka A.
        • Ishida Y.
        • Wong L.S.
        • Seidel J.A.
        • Nonomura Y.
        • et al.
        Pituitary adenylate cyclase-activating polypeptide promotes cutaneous dendritic cell functions in contact hypersensitivity.
        J Allergy Clin Immunol. 2021; 148: 858-866
        • Yin Q.
        • Sun L.
        • Cai X.
        • Lou F.
        • Sun Y.
        • Wang B.
        • et al.
        Lidocaine ameliorates psoriasis by obstructing pathogenic CGRP signaling‒mediated sensory neuron‒dendritic cell communication.
        J Invest Dermatol. 2022; 142: 2173-2183.e6
        • Zeisel A.
        • Hochgerner H.
        • Lönnerberg P.
        • Johnsson A.
        • Memic F.
        • van der Zwan J.
        • et al.
        Molecular architecture of the mouse nervous system.
        Cell. 2018; 174: 999-1014.e22
        • Zhan M.
        • Zheng W.
        • Jiang Q.
        • Zhao Z.
        • Wang Z.
        • Wang J.
        • et al.
        Upregulated expression of substance P (SP) and NK1R in eczema and SP-induced mast cell accumulation.
        Cell Biol Toxicol. 2017; 33: 389-405
        • Zhang X.
        • He Y.
        The role of nociceptive neurons in the pathogenesis of psoriasis.
        Front Immunol. 2020; 11: 1984

      Supplementary References

        • Follansbee T.
        • Zhou Y.
        • Wu X.
        • Delahanty J.
        • Nguyen A.
        • Domocos D.
        • et al.
        Signs of chronic itch in the mouse imiquimod model of psoriasiform dermatitis: sex differences and roles of TRPV1 and TRPA1.
        Itch (Phila). 2019; 4 (e25)
        • Li L.
        • Liu X.
        • Ge W.
        • Chen C.
        • Huang Y.
        • Jin Z.
        • et al.
        CB2R deficiency exacerbates imiquimod-induced psoriasiform dermatitis and itch through the neuro-immune pathway.
        Front Pharmacol. 2022; 13: 790712
        • Liu X.
        • Wang X.
        • Duan X.
        • Poorun D.
        • Xu J.
        • Zhang S.
        • et al.
        Lipoxin A4 and its analog suppress inflammation by modulating HMGB1 translocation and expression in psoriasis.
        Sci Rep. 2017; 7: 7100
        • Oishi N.
        • Iwata H.
        • Kambe N.
        • Kobayashi N.
        • Fujimoto K.
        • Sato H.
        • et al.
        Expression of precipitating factors of pruritus found in humans in an imiquimod-induced psoriasis mouse model.
        Heliyon. 2019; 5e01981
        • Sakai K.
        • Sanders K.M.
        • Youssef M.R.
        • Yanushefski K.M.
        • Jensen L.
        • Yosipovitch G.
        • et al.
        Mouse model of imiquimod-induced psoriatic itch.
        Pain. 2016; 157: 2536-2543