Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA.
Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA; Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, CA 92093, USA.
J Autoimmun. 2024 Apr;144:103177. doi: 10.1016/j.jaut.2024.103177. Epub 2024 Feb 17.
Psoriasis (PS) and atopic dermatitis (AD) are common skin inflammatory diseases characterized by hyper-responsive keratinocytes. Although, some cytokines have been suggested to be specific for each disease, other cytokines might be central to both diseases. Here, we show that Tumor necrosis factor superfamily member 14 (TNFSF14), known as LIGHT, is required for experimental PS, similar to its requirement in experimental AD. Mice devoid of LIGHT, or deletion of either of its receptors, lymphotoxin β receptor (LTβR) and herpesvirus entry mediator (HVEM), in keratinocytes, were protected from developing imiquimod-induced psoriatic features, including epidermal thickening and hyperplasia, and expression of PS-related genes. Correspondingly, in single cell RNA-seq analysis of PS patient biopsies, LTβR transcripts were found strongly expressed with HVEM in keratinocytes, and LIGHT was upregulated in T cells. Similar transcript expression profiles were also seen in AD biopsies, and LTβR deletion in keratinocytes also protected mice from allergen-induced AD features. Moreover, in vitro, LIGHT upregulated a broad spectrum of genes in human keratinocytes that are clinical features of both PS and AD skin lesions. Our data suggest that agents blocking LIGHT activity might be useful for therapeutic intervention in PS as well as in AD.
银屑病（PS）和特应性皮炎（AD）是常见的皮肤炎症性疾病，其特征为角质形成细胞超敏反应。虽然有些细胞因子被认为是每种疾病所特有的，但其他细胞因子可能对两种疾病都很重要。在这里，我们表明肿瘤坏死因子超家族成员 14（TNFSF14），也称为 LIGHT，是实验性 PS 所必需的，与实验性 AD 中的要求相似。缺乏 LIGHT 的小鼠，或缺失其受体，即淋巴毒素β受体（LTβR）和疱疹病毒进入介体（HVEM）的角质形成细胞，可防止咪喹莫特诱导的银屑病特征的发展，包括表皮增厚和增生，以及 PS 相关基因的表达。相应地，在 PS 患者活检的单细胞 RNA-seq 分析中，发现 LTβR 转录物在角质形成细胞中与 HVEM 强烈表达，而 LIGHT 在 T 细胞中上调。AD 活检中也观察到类似的转录表达谱，并且角质形成细胞中 LTβR 的缺失也可保护小鼠免受过敏原诱导的 AD 特征。此外，在体外，LIGHT 上调了人类角质形成细胞中广泛的基因，这些基因是 PS 和 AD 皮肤损伤的临床特征。我们的数据表明，阻断 LIGHT 活性的药物可能对 PS 和 AD 的治疗干预有用。
