Sensory neuroimmune signaling in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis - 18/11/24

Doi : 10.1016/j.jaci.2024.10.015

Xiaobao Huang, MD ^a,^b, Suiting Ao, MD ^a,^c,^d, Rui Xu, MD, PhD ^a, Xuemei Gao, MD ^a,^e, Shiling Qi, MD, PhD ^f, Yarong Liang, MB ^b, Peiying Feng, MD, PhD ^g, Ruzeng Xue, MD ^h, Yingying Ren, MD ^h, Jiande Han, MD ^a, Fengxian Li, MD, PhD ⁱ, Coco Chu, PhD ^j,^k,^l,^⁎ , Fang Wang, MD, PhD ^a,^h,^m,^⁎
^a Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
^b Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
^c Hospital for Skin Diseases, Shandong First Medical University, Jinan, China
^d Shandong Provincial lnstitute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, China
^e Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
^f Department of Dermatology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
^g Department of Dermatology & Allergy, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
^h Dermatology Hospital, Southern Medical University, Guangzhou, China
ⁱ Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
^j Laboratory of Neuroimmunology, Institute for Immunology, School of Basic Medical Sciences, Tsinghua University, Beijing, China
^k Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
^l SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua University, Beijing, China
^m Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong, China

^∗Corresponding authors: Fang Wang, MD, PhD, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Er Rd, Guangzhou, Guangdong 510080, China.The First Affiliated HospitalSun Yat-sen University58 Zhongshan Er RdGuangzhouGuangdong510080China^∗Coco Chu, PhD, Tsinghua University, Beijing 100084, China.Tsinghua UniversityBeijing100084China

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Graphical abstract

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Abstract

Background

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.

Objective

We investigated the potential neuroimmune regulation in SJS/TEN.

Methods

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.

Results

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.

Conclusions

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.

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Key words : Cutaneous adverse drug reactions, CD8⁺ T cell, sensory, neuropeptide, calcitonin gene–related peptide, cytokine receptor, cytotoxicity

Abbreviations used : BP, CGRP, HC, HCN, IF, IVA, RAMP1, scRNA-seq, SJS, T_EFF, T_EM, TEN