Effect of opioid receptor antagonist on mitigating tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis

IF 7.9 1区 医学 Q1 IMMUNOLOGY
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Abstract

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.

Abstract Image

阿片受体拮抗剂对减轻肿瘤坏死因子样细胞凋亡弱诱导剂(TWEAK)诱导的天疱疮发病机制中细胞凋亡的影响
丘疹性荨麻疹是一种严重的自身免疫性水疱病,其特征是由针对去疱疹素 1 和 3(DSG1/3)的自身抗体引发的棘层溶解。细胞凋亡在促进棘层溶解方面起着关键作用,但其确切的内在机制仍不清楚。众所周知,肿瘤坏死因子样细胞凋亡弱诱导因子(TWEAK)可促进细胞凋亡并破坏细胞连接,但它在丘疹性荨麻疹发病机制中的作用仍不明确。我们的研究观察到,DSG1/3表达减少的同时,TWEAK/成纤维细胞生长因子诱导14(Fn14)表达增加,病变和周围皮肤的角质细胞凋亡也增加。体外实验显示,TWEAK 刺激的角质形成细胞表现出更强的凋亡、STAT1 磷酸化和细胞间 DSG1/3 表达减少。值得注意的是,大量 RNA 测序揭示了 CASPASE-3 负责介导 DSG1/3 的消耗,在共沉淀试验中与 DSG1/3 的直接相互作用也证实了这一点。纳洛酮以保持细胞粘附性和防止细胞死亡而闻名,它能有效减少细胞凋亡,并恢复 TWEAK 刺激的角质形成细胞中 DSG1/3 的水平。纳洛酮的抗凋亡特性在小鼠丘疹性荨麻疹模型中得到了进一步验证。我们的研究结果阐明,TWEAK 通过增强 caspase-3 的活性促进角质形成细胞的凋亡,从而导致丘疹性荨麻疹中 DSG1/3 的耗竭和细胞凋亡。重要的是,纳洛酮可以对抗TWEAK在丘疹性荨麻疹发病机制中诱导的细胞凋亡,从而提供一种潜在的治疗干预。
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来源期刊
Journal of autoimmunity
Journal of autoimmunity 医学-免疫学
CiteScore
27.90
自引率
1.60%
发文量
117
审稿时长
17 days
期刊介绍: The Journal of Autoimmunity serves as the primary publication for research on various facets of autoimmunity. These include topics such as the mechanism of self-recognition, regulation of autoimmune responses, experimental autoimmune diseases, diagnostic tests for autoantibodies, as well as the epidemiology, pathophysiology, and treatment of autoimmune diseases. While the journal covers a wide range of subjects, it emphasizes papers exploring the genetic, molecular biology, and cellular aspects of the field. The Journal of Translational Autoimmunity, on the other hand, is a subsidiary journal of the Journal of Autoimmunity. It focuses specifically on translating scientific discoveries in autoimmunity into clinical applications and practical solutions. By highlighting research that bridges the gap between basic science and clinical practice, the Journal of Translational Autoimmunity aims to advance the understanding and treatment of autoimmune diseases.
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