Mas相关G蛋白偶联受体X2在特应性皮炎瘙痒中的研究进展

doi:10.35541/cjd.20230078

Abstract

Abstract: 【Abstract】 Atopic dermatitis is a chronic recurrent inflammatory skin disease, and often accompanied by severe itch, which greatly affects the quality of life of patients. Mas-related G protein-coupled receptor X2 is a multi-ligand receptor highly expressed on mast cells. It can respond to a variety of exogenous and endogenous stimuli, trigger mast cell degranulation and promote inflammatory mediator release through various signaling cascades, and play an important role in the occurrence and development of atopic dermatitis. This review summarizes current understanding on mechanisms of action of Mas-related G protein-coupled receptor X2 in atopic dermatitis-associated itch, as wellas related drug inhibitors, in order to provide a theoretical basis for the treatment of atopic dermatitis-associated itch.

Key words: Dermatitis, atopic, Pruritus, Mast cells, MRGPRX2, Signal transduction

Yang Lei, Zheng Gaofeng, Chu Lei, Ran Yuping. Mas-related G protein-coupled rceptor X2 in itch in atopic dermatitis[J]. Chinese Journal of Dermatology,2023,e0230078. doi:10.35541/cjd.20230078

References ［37］

［1］	David Boothe W, Tarbox JA, Tarbox MB. Atopic dermatitis: pathophysiology［J］. Adv Exp Med Biol, 2017,1027:21⁃37. doi: 10.1007/978⁃3⁃319⁃64804⁃0_3.
［2］	Tatemoto K, Nozaki Y, Tsuda R, et al. Immunoglobulin E⁃independent activation of mast cell is mediated by Mrg receptors［J］. Biochem Biophys Res Commun, 2006,349（4）:1322⁃1328. doi: 10.1016/j.bbrc.2006.08.177.
［3］	Motakis E, Guhl S, Ishizu Y, et al. Redefinition of the human mast cell transcriptome by deep⁃CAGE sequencing［J］. Blood, 2014,123（17）:e58⁃e67. doi: 10.1182/blood⁃2013⁃02⁃483792.
［4］	Langan SM, Irvine AD, Weidinger S. Atopic dermatitis［J］. Lancet, 2020,396（10247）:345⁃360. doi: 10.1016/S0140⁃6736（20）31286⁃1.
［5］	Pavlis J, Yosipovitch G. Management of itch in atopic dermatitis［J］. Am J Clin Dermatol, 2018,19（3）:319⁃332. doi: 10.1007/s40257⁃017⁃0335⁃4.
［6］	Roy S, Chompunud Na Ayudhya C, Thapaliya M, et al. Multifaceted MRGPRX2: new insight into the role of mast cells in health and disease［J］. J Allergy Clin Immunol, 2021,148（2）:293⁃308. doi: 10.1016/j.jaci.2021.03.049.
［7］	Subramanian H, Gupta K, Lee D, et al. β⁃Defensins activate human mast cells via Mas⁃related gene X2［J］. J Immunol, 2013,191（1）:345⁃352. doi: 10.4049/jimmunol.1300023.
［8］	Reddy VB, Azimi E, Chu L, et al. Mas⁃related G⁃protein coupled receptors and Cowhage⁃induced itch［J］. J Invest Dermatol, 2018,138（2）:461⁃464. doi: 10.1016/j.jid.2017.05.042.
［9］	Kühn H, Kolkhir P, Babina M, et al. Mas⁃related G protein⁃coupled receptor X2 and its activators in dermatologic allergies［J］. J Allergy Clin Immunol, 2021,147（2）:456⁃469. doi: 10. 1016/j.jaci.2020.08.027.
［10］	Ogasawara H, Furuno M, Edamura K, et al. Peptides of major basic protein and eosinophil cationic protein activate human mast cells［J］. Biochem Biophys Rep, 2020,21:100719. doi: 10.1016/j.bbrep.2019.100719.
［11］	Cao C, Kang HJ, Singh I, et al. Structure, function and pharmacology of human itch GPCRs［J］. Nature, 2021,600（7887）:170⁃175. doi: 10.1038/s41586⁃021⁃04126⁃6.
［12］	Mi YN, Ping NN, Cao YX. Ligands and signaling of Mas⁃related G protein⁃coupled receptor⁃X2 in mast cell activation［J］. Rev Physiol Biochem Pharmacol, 2021,179:139⁃188. doi: 10.1007/112_2020_53.
［13］	Wang X, Zhang F, Chen F, et al. MEKK3 regulates IFN⁃gamma production in T cells through the Rac1/2⁃dependent MAPK cascades［J］. J Immunol, 2011,186（10）:5791⁃5800. doi: 10. 4049/jimmunol.1002127.
［14］	Liu R, Che D, Zhao T, et al. MRGPRX2 is essential for sinomenine hydrochloride induced anaphylactoid reactions［J］. Biochem Pharmacol, 2017,146:214⁃223. doi: 10.1016/j.bcp.2017. 09.017.
［15］	Shi X, Wang L, Clark JD, et al. Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways［J］. Regul Pept, 2013,186:92⁃103. doi: 10.1016/j.regpep.2013.08.001.
［16］	Dinallo V, Marafini I, Di Fusco D, et al. Neutrophil extracellular traps sustain inflammatory signals in ulcerative colitis［J］. J Crohns Colitis, 2019,13（6）:772⁃784. doi: 10.1093/ecco⁃jcc/jjy215.
［17］	Lee HS, Kim EN, Kim GR, et al. Persimmon leaf extract protects mice from atopic dermatitis by inhibiting T cell activation via regulation of the JNK pathway［J］. Phytother Res, 2021. doi: 10.1002/ptr.6985.
［18］	Gu Y, Yang DK, Spinas E, et al. Role of TNF in mast cell neuroinflammation and pain［J］. J Biol Regul Homeost Agents, 2015,29（4）:787⁃791.
［19］	Metcalfe DD, Peavy RD, Gilfillan AM. Mechanisms of mast cell signaling in anaphylaxis［J］. J Allergy Clin Immunol, 2009,124（4）:639⁃646; quiz 647⁃648. doi: 10.1016/j.jaci.2009.08.035.
［20］	Okayama Y, Tkaczyk C, Metcalfe DD, et al. Comparison of Fc epsilon RI⁃ and Fc gamma RI⁃mediated degranulation and TNF⁃alpha synthesis in human mast cells: selective utilization of phosphatidylinositol⁃3⁃kinase for Fc gamma RI⁃induced degranulation［J］. Eur J Immunol, 2003,33（5）:1450⁃1459. doi: 10.1002/eji.200323563.
［21］	Ogasawara H, Noguchi M. Therapeutic potential of MRGPRX2 inhibitors on mast cells［J］. Cells, 2021,10（11）:1⁃21. doi: 10. 3390/cells10112906.
［22］	Zeng D, Chen C, Zhou W, et al. TRPA1 deficiency alleviates inflammation of atopic dermatitis by reducing macrophage infiltration［J］. Life Sci, 2021,266:118906. doi: 10.1016/j.lfs. 2020.118906.
［23］	Raguz J, Jeric I, Niault T, et al. Epidermal RAF prevents allergic skin disease［J］. Elife, 2016,5:1⁃24. doi: 10.7554/eLife.14012. 001.
［24］	Azimi E, Reddy VB, Shade KC, et al. Dual action of neurokinin⁃1 antagonists on Mas⁃related GPCRs［J］. JCI Insight, 2016,1（16）:e89362. doi: 10.1172/jci.insight.89362.
［25］	Ogasawara H, Furuno M, Edamura K, et al. Novel MRGPRX2 antagonists inhibit IgE⁃independent activation of human umbilical cord blood⁃derived mast cells［J］. J Leukoc Biol, 2019,106（5）:1069⁃1077. doi: 10.1002/JLB.2AB1018⁃405R.
［26］	Hou Y, Che D, Ma P, et al. Anti⁃pseudo⁃allergy effect of isoliquiritigenin is MRGPRX2⁃dependent［J］. Immunol Lett, 2018,198:52⁃59. doi: 10.1016/j.imlet.2018.04.004.
［27］	Wang J, Zhang Y, Li C, et al. Inhibitory function of Shikonin on MRGPRX2⁃mediated pseudo⁃allergic reactions induced by the secretagogue［J］. Phytomedicine, 2020,68:153149. doi: 10.1016/j.phymed.2019.153149.
［28］	Wang N, Wang J, Zhang Y, et al. Imperatorin ameliorates mast cell⁃mediated allergic airway inflammation by inhibiting MRGPRX2 and CamKII/ERK signaling pathway［J］. Biochem Pharmacol, 2021,184:114401. doi: 10.1016/j.bcp.2020.114401.
［29］	Qiao C, Hu S, Che D, et al. The anti⁃anaphylactoid effects of Piperine through regulating MAS⁃related G protein⁃coupled receptor X2 activation［J］. Phytother Res, 2020,34（6）:1409⁃1420. doi: 10.1002/ptr.6615.
［30］	Wang J, Zhang Y, Wang J, et al. Paeoniflorin inhibits MRGPRX2⁃mediated pseudo⁃allergic reaction via calcium signaling pathway［J］. Phytother Res, 2020,34（2）:401⁃408. doi: 10.1002/ptr.6531.
［31］	Yao C, Ye W, Chen M. Inhibition of mast cell degranulation in atopic dermatitis by celastrol through suppressing MRGPRX2［J］. Dis Markers, 2023,2023:9049256. doi: 10.1155/2023/9049 256.
［32］	Vander Does A, Ju T, Mohsin N, et al. How to get rid of itching［J］. Pharmacol Ther, 2023,243:108355. doi: 10.1016/j.pharmthera.2023.108355.
［33］	Suzuki Y, Liu S, Ogasawara T, et al. A novel MRGPRX2⁃targeting antagonistic DNA aptamer inhibits histamine release and prevents mast cell⁃mediated anaphylaxis［J］. Eur J Pharmacol, 2020,878:173104. doi: 10.1016/j.ejphar.2020.173104.
［34］	Wang J, Zhang Y, Hu S, et al. Resveratrol inhibits MRGPRX2⁃mediated mast cell activation via Nrf2 pathway［J］. Int Immunopharmacol, 2021,93:107426. doi: 10.1016/j.intimp.2021. 107426.
［35］	Huang Y, Huang L, Zhu G, et al. Downregulated microRNA⁃27b attenuates lipopolysaccharide⁃induced acute lung injury via activation of NF⁃E2⁃related factor 2 and inhibition of nuclear factor κB signaling pathway［J］. J Cell Physiol, 2019,234（5）:6023⁃6032. doi: 10.1002/jcp.27187.
［36］	Yang N, Ju Y, Huang D, et al. Desensitization of TRPV1 involved in the antipruritic effect of osthole on histamine⁃induced scratching behavior in mice［J］. Evid Based Complement Alternat Med, 2021,2021:4012812. doi: 10.1155/2021/4012812.
［37］	Yamada K, Sato H, Sakamaki K, et al. Suppression of IgE⁃independent degranulation of murine connective tissue⁃type mast cells by dexamethasone［J］. Cells, 2019,8（2）:112. doi: 10. 3390/cells8020112.

[1]	Li Ming, Li Yan, Li Linfeng. JAK inhibitors for the treatment of moderate-to-severe atopic dermatitis [J]. Chinese Journal of Dermatology, 2025, 0(3): 20220342-e0220342.
[2]	Zhang Beilei, Song Xiuzu. Etiology and pathogenesis of sensitive scalp [J]. Chinese Journal of Dermatology, 2025, 0(3): 20240301-e20240301.
[3]	Song Pu, Liu Yu, Guo Sen, Li Shuli, Liu Ling, Li Chunying. Mast cell-derived chemokine C-C motif ligand 5 affects the migration of CD8⁺ T cells in vitiligo under oxidative stress [J]. Chinese Journal of Dermatology, 2025, 0(2): 20230513-e20230513.
[4]	Zhu Ping, Wang Daguang. Metastatic mechanisms of cutaneous squamous cell carcinoma [J]. Chinese Journal of Dermatology, 2025, 58(2): 186-189.
[5]	Huang Xiaoyan, Su Juan, Chen Mingliang, Chen Xiang, Xiao Yi, Shen Minxue, . Efficacy of naloxone in improving health-related quality of life in patients with chronic arsenic exposure-related pruritus: a randomized, double-blind, placebo-controlled trial [J]. Chinese Journal of Dermatology, 2025, 58(2): 161-166.
[6]	Li Qianwen, Liao Zhikai, Le Yue, Duan Bolin, Geng Mengmeng, Lei Tiechi. The antioxidant Tempol inhibits pigment loss in tail skin of a mouse model of immune-induced vitiligo under oxidative stress [J]. Chinese Journal of Dermatology, 2025, 58(2): 126-131.
[7]	Chinese Association of Rehabilitation Dermatology, Working Group on Geriatric Dermatology, Combination of Traditional and Western Medicine Dermatology. Expert consensus on the diagnosis, treatment, and rehabilitation of pruritus in the elderly （2025 edition） [J]. Chinese Journal of Dermatology, 2025, 58(1): 1-8.
[8]	China Dermatologist Association. Guidelines for the management of chronic pruritus （2024） [J]. Chinese Journal of Dermatology, 2024, 57(5): 387-399.
[9]	Guo Lan, Jin Hongzhong. Small-molecule/biological agents in the treatment of pruritus [J]. Chinese Journal of Dermatology, 2024, 57(5): 475-478.
[10]	Xu Zhuohong, Zhou Xuyue, Hu Yu, Gu Heng. Role of mast cells in the pathogenesis of chronic spontaneous urticaria and advances in mast cell-targeted therapies [J]. Chinese Journal of Dermatology, 2024, 0(3): 20240291-e20240291.
[11]	Yuan Liyan, Yu Xiaoling, Wang Xiaohua, Yang Bin. TYK2 inhibitors for plaque psoriasis: mechanism of action and advances in clinical research [J]. Chinese Journal of Dermatology, 2024, 0(3): 20220740-e0220740.
[12]	Xu Jingwei, Chen Shuang, Guo Kelei, Han Li, Bian Hua, . MicroRNAs regulating signaling pathways related to systemic scleroderma fibrosis [J]. Chinese Journal of Dermatology, 2024, 0(3): 20230730-e20230730.
[13]	Zheng Yaxuan, Su Huichun. Role of sweat in the pathogenesis of cholinergic urticaria [J]. Chinese Journal of Dermatology, 2024, 0(3): 20230055-e20230055.
[14]	He Xingyan, Zhang Kejia, Feng Yanyan. Noval G protein-coupled receptor X2 in dermatology [J]. Chinese Journal of Dermatology, 2024, 0(3): 20240124-e20240124.
[15]	Xia Dengmei, Zhou Xingli, Wang Mi, Feng Xun, Li Jishu, Wang Yiyi, Li Xiaohong, Li Wei. Retrospective analysis of 13 patients with epidermolysis bullosa acquisita [J]. Chinese Journal of Dermatology, 2024, 57(10): 910-916.

Mas-related G protein-coupled rceptor X2 in itch in atopic dermatitis

PDF

PDF (Mobile)

Knowledge

Abstract

Cite this article

share this article

References ［37］

Related Articles 15

Metrics

Comments

Recommended 10