Huang Xiaobao, Ao Suiting, Xu Rui, Gao Xuemei, Qi Shiling, Liang Yarong, Feng Peiying, Xue Ruzeng, Ren Yingying, Han Jiande, Li Fengxian, Chu Coco, Wang Fang
Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Hospital for Skin Diseases, Shandong First Medical University, Jinan, China; Shandong Provincial lnstitute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China.
J Allergy Clin Immunol. 2025 Feb;155(2):533-546. doi: 10.1016/j.jaci.2024.10.015. Epub 2024 Oct 29.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions often triggered by medications. While the involvement of CD8 T cells causing keratinocyte death is well recognized, the contribution of neural elements to the persistent skin inflammation has been largely overlooked.
We investigated the potential neuroimmune regulation in SJS/TEN.
Unbiased single-cell RNA sequencing and flow cytometry were performed using circulating CD8 T cells from healthy controls and patients with SJS/TEN. ELISA and LEGENDplex assays were respectively used to detect neuropeptides and inflammatory mediators. Skin tissues were examined by immunofluorescence staining for neuropeptide-associated nerves and cytokine receptors. Calcium imaging, Smart-seq, and a 3-D skin model were used for cultured human CD8 T cells.
Unbiased RNA sequencing revealed an upregulation of the receptor for neuropeptide calcitonin gene-related peptide (CGRP), known as RAMP1, in effector CD8 T cells in SJS/TEN. Increased CGRP nerve fibers and CGRP levels, along with upregulated IL-15R and IL-18R on CD8 T cells, were displayed in the affected skin of SJS/TEN. The CGRP-RAMP1 axis was necessary and sufficient to enhance receptors for IL-15 and IL-18 and cytotoxic activities in CD8 T cells, ultimately resulting in keratinocyte apoptosis. Calcium influx was detected in CGRP-stimulated CD8 T cells. HCN2, a hyperpolarization-activated cation channel, was required for this process and the subsequent cytotoxic effects.
Our study highlights the role of neural elements in regulating CD8 T-cell-mediated inflammatory responses and provides new potential translational targets to improve the outcomes of severe cutaneous drug reactions.
史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）是常由药物引发的危及生命的皮肤反应。虽然人们已经充分认识到CD8 T细胞参与导致角质形成细胞死亡，但神经成分对持续性皮肤炎症的作用在很大程度上被忽视了。
我们研究了SJS/TEN中潜在的神经免疫调节。
使用来自健康对照和SJS/TEN患者的循环CD8 T细胞进行无偏倚单细胞RNA测序和流式细胞术。分别使用ELISA和LEGENDplex检测法检测神经肽和炎症介质。通过免疫荧光染色检查皮肤组织中的神经肽相关神经和细胞因子受体。对培养的人CD8 T细胞进行钙成像、Smart-seq和三维皮肤模型实验。
无偏倚RNA测序显示，SJS/TEN效应CD8 T细胞中神经肽降钙素基因相关肽（CGRP）的受体RAMP1上调。在SJS/TEN的受累皮肤中，CGRP神经纤维和CGRP水平增加，同时CD8 T细胞上的IL-15R和IL-18R上调。CGRP-RAMP1轴对于增强CD8 T细胞中IL-15和IL-18的受体以及细胞毒性活性是必要且充分的，最终导致角质形成细胞凋亡。在CGRP刺激的CD8 T细胞中检测到钙内流。超极化激活阳离子通道HCN2参与了这一过程及随后的细胞毒性作用。
我们的研究突出了神经成分在调节CD8 T细胞介导的炎症反应中的作用，并为改善严重皮肤药物反应的结果提供了新的潜在转化靶点。
