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.

中文翻译：

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感觉神经免疫信号在 Stevens-Johnson 综合征和中毒性表皮坏死松解症的发病机制中的作用。


背景 Stevens-Johnson 综合征 （SJS） 和中毒性表皮坏死松解症 （TEN） 是危及生命的皮肤反应，通常由药物引发。虽然 CD8+ T 细胞参与导致角质形成细胞死亡已得到广泛认可，但神经元件对持续性皮肤炎症的贡献在很大程度上被忽视了。目的 我们研究了 SJS/TEN 中潜在的神经免疫调节。方法 使用来自健康对照和 SJS/TEN 患者的循环 CD8+ T 细胞进行无偏倚的单细胞 RNA 测序和流式细胞术。ELISA 和 LEGENDplex 检测分别用于检测神经肽和炎症介质。通过免疫荧光染色检查皮肤组织神经肽相关神经和细胞因子受体。钙成像、 Smart-seq 和 3-D 皮肤模型用于培养的人 CD8+ T 细胞。结果 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） 受体（称为 RAMP1）上调。在 SJS/TEN 受影响的皮肤中显示 CGRP+ 神经纤维和 CGRP 水平增加，以及 CD8+ T 细胞上 IL-15R 和 IL-18R 上调。CGRP-RAMP1 轴对于增强 CD8+ T 细胞中的 IL-15 和 IL-18 受体以及细胞毒活性是必要且足够的，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。HCN2 是一种超极化激活的阳离子通道，是此过程和随后的细胞毒性作用所必需的。 结论 我们的研究强调了神经元件在调节 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预后提供了新的潜在转化靶点。