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The key role of CB1R in the sensory neurons to regulate psoriasiform skin inflammation and pruritus

  • Author Footnotes
    # These authors have contributed equally to this work
    Xin Liu
    Footnotes
    # These authors have contributed equally to this work
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China
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  • Author Footnotes
    # These authors have contributed equally to this work
    Li Li
    Footnotes
    # These authors have contributed equally to this work
    Affiliations
    Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, XiWu Road No.157, Xi’an, Shanxi Province, 710004, China
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  • Jian Jiang
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China
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  • Wenqiang Ge
    Affiliations
    Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, HangKong Road No.13, Wuhan, Hubei Province, 430030, China
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  • Yuqiong Huang
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China
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  • Zilin Jin
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China
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  • XinXin Liu
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China
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  • Yi Kong
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China
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  • Ouyang Zhanmu
    Affiliations
    Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, HangKong Road No.13, Wuhan, Hubei Province, 430030, China
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  • Xin Zeng
    Affiliations
    Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, TaoYuan Road No.89, Shenzhen, Guangdong Province, 518052, China
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  • Fei Li
    Affiliations
    Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, TaoYuan Road No.89, Shenzhen, Guangdong Province, 518052, China
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  • Man Li
    Affiliations
    Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, HangKong Road No.13, Wuhan, Hubei Province, 430030, China
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  • Hongxiang Chen
    Correspondence
    Corresponding author: Hongxiang Chen, PhD, Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1277, Jiefang Avenue, Wuhan, Hubei Province, 430030, China; Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, Shenzhen 518052, China, Tel: 0086-13871022932, Fax: 0086 27-83694168, .
    Affiliations
    Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, JieFang Avenue No.1277, Wuhan, Hubei Province, 430030, China

    Department of Dermatology, Union Shenzhen Hospital, Huazhong University of Science and Technology, TaoYuan Road No.89, Shenzhen, Guangdong Province, 518052, China
    Search for articles by this author
  • Author Footnotes
    # These authors have contributed equally to this work
Published:November 18, 2022DOI:https://doi.org/10.1016/j.jid.2022.10.014

      ABSTRACT

      Type I cannabinoid receptor (CB1R) has been reported to exhibit favorable anti-inflammation and anti-pruritus 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 psoriatic mouse model, while CB1R antagonist aggravated these symptoms. As the expression of CB1R was abundant in dorsal root ganglia (DRG), we constructed mice with conditional CB1R knockout (CB1R-cKO) in primary sensory neurons and found that imiquimod (IMQ) induced psoriasiform inflammation and itch were both worsened in CB1R-cKO mice. Next, we observed that the CB1R mostly located in peptidergic neurons and deletion of CB1R in primary sensory neurons promoted the production and release of substance P (SP) to the skin tissue. Furthermore, the elevated SP in the skin affected the activation of ERK in keratinocytes and induced the accumulation of mast cells in the dermis. Last, we demonstrated that blocking the SP signal significantly alleviated the exacerbation of psoriasiform inflammation and itch caused by IMQ in CB1R-cKO mice. Together, our work reveals that CB1R in sensory neurons plays a key role in psoriasiform skin inflammation and pruritus via regulating SP expression.

      Graphical abstract

      Key words

      Abbreviations:

      Adv (advillin), BDNF (brain-derived neurotrophic factor), CB1R (type I cannabinoid receptor), CB1R-cKO (conditional CB1R knockout), CBRs (cannabinoid receptors), CCK (cholecystokinin), CGRP (calcitonin gene-related peptide), DRG (dorsal root ganglia), ECS (endocannabinoid system), ERK (extracellular signal-regulated kinase), GRP (gastrin-releasing peptide), IMQ (imiquimod), NP (non-peptidergic), NK1R (neurokinin-1 receptor), PACAP (pituitary adenylate cyclase-activating polypeptide), SP (substance P), TMX (tamoxifen), 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.
        Nature communications. 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 in pharmacological sciences. 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.
        Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 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 (e16): 301-317
        • 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 (e14): 919-932
        • Davis M.P.
        Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands.
        Expert opinion on investigational 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.
        Inflammation research : official journal of the European Histamine Research Society [et al]. 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.
        Journal of the European Academy of Dermatology and Venereology : JEADV. 2019; 33: 1465-1476
        • Farber E.M.
        • Lanigan S.W.
        • Boer J.
        The role of cutaneous sensory nerves in the maintenance of psoriasis.
        International journal of dermatology. 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 (e3): 412-420
        • 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 : international journal of phytotherapy and phytopharmacology. 2022; 95153864
      1. 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(1-2):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.
        International journal of dermatology. 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.
        Annual review of medicine. 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.
        Molecular pain. 2011; 7: 100
        • Lay M.
        • Dong X.
        Neural Mechanisms of Itch.
        Annual review of neuroscience. 2020; 43: 187-205
      2. Lee SH, Tonello R, Choi Y, Jung SJ, 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(11):2221-9.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.
        Frontiers in pharmacology. 2022; 13790712
        • 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.
        Frontiers in pharmacology. 2021; 12781237
        • 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 (e5): 1163-1171
        • 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 Ca(2+) Flux in T-Cell-Receptor-Activated T Cells.
        Cell Rep. 2020; 30 (e8): 3448-3465
        • 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.
        The Journal of investigative dermatology. 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.
        The Journal of dermatological treatment. 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.
        Frontiers in cellular neuroscience. 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 innovations : skin science from molecules to population health. 2022; 2100095
        • 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
        • Stander 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.
        Current problems in dermatology. 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 dermato-venereologica. 2017; 97: 639-641
        • Wang W.
        • Wang H.
        • Zhao Z.
        • Huang X.
        • Xiong H.
        • Mei Z.
        Thymol activates TRPM8-mediated Ca(2+) influx for its antipruritic effects and alleviates inflammatory response in Imiquimod-induced mice.
        Toxicology and applied pharmacology. 2020; 407115247
        • 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.
        The Journal of allergy and clinical immunology. 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;
        • 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 (e22): 999-1014
        • 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.
        Frontiers in immunology. 2020; 11: 1984