伤害感受器衍生的降钙素基因相关肽增强皮肤I型传统树突状细胞功能，以驱动白癜风中的自身反应性CD8 T细胞反应。

Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8 T cell responses in vitiligo.

作者信息

Yang Xiuli, Ding Wenxiang, Lou Fangzhou, Xu Hao, Sheng Anqi, Sun Yang, Cai Xiaojie, Zhou Miaoni, Lin Fuquan, Jin Rong, Zheng Xichen, Wang Zhikai, Deng Siyu, Xu Zhenyao, Zhang Taiyu, Cheng Jinke, Zheng Xingdong, Xu Aie, Wang Honglin

机构信息

Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

出版信息

Immunity. 2025 Aug 12;58(8):2086-2103.e9. doi: 10.1016/j.immuni.2025.05.018. Epub 2025 Jun 16.

DOI:10.1016/j.immuni.2025.05.018

PMID:40527324

Abstract

Vitiligo is an autoimmune disease characterized by depigmented patches of skin. Autoreactive CD8 T cells kill melanocytes in vitiligo, but the immunopathogenesis remains elusive and ideal drug targets are lacking. Through single-cell and spatial transcriptomic analysis of vitiligo lesional skin, we found that conventional type 1 dendritic cells (cDC1s) primed CD8 T cells and highly expressed the neuropeptide calcitonin gene-related peptide (CGRP) receptor. Deletion of Na1.8 nociceptors, cDC1-specific ablation of the CGRP receptor, or treatment with a CGRP receptor antagonist (rimegepant) abrogated CD8 T cell autoreactivity and prevented skin depigmentation in a mouse model of vitiligo. Conversely, CGRP administration restored vitiligo development in nociceptor-ablated mice. In a pilot study, topical application of rimegepant ointment alleviated skin depigmentation in individuals with vitiligo. Taken together, our results reveal that nociceptor-derived CGRP promotes cDC1-CD8 T cell interactions and highlight CGRP receptor antagonism as a potential therapeutic strategy for treating vitiligo.

摘要

白癜风是一种自身免疫性疾病，其特征是皮肤出现色素脱失斑。自身反应性CD8 T细胞在白癜风中杀死黑素细胞，但免疫发病机制仍不清楚，且缺乏理想的药物靶点。通过对白癜风皮损皮肤进行单细胞和空间转录组分析，我们发现传统1型树突状细胞（cDC1s）启动CD8 T细胞并高表达神经肽降钙素基因相关肽（CGRP）受体。在白癜风小鼠模型中，缺失Na1.8伤害感受器、cDC1特异性敲除CGRP受体或用CGRP受体拮抗剂（利美尼定）治疗可消除CD8 T细胞的自身反应性并防止皮肤色素脱失。相反，给予CGRP可恢复伤害感受器切除小鼠的白癜风发展。在一项初步研究中，局部应用利美尼定软膏可减轻白癜风患者的皮肤色素脱失。综上所述，我们的结果表明伤害感受器衍生的CGRP促进cDC1-CD8 T细胞相互作用，并突出了CGRP受体拮抗作用作为治疗白癜风的潜在治疗策略。