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

• Published in: Journal of autoimmunity Vol. 149; p. 103307
• Main Authors: Peng, Xueting, Wang, Sijia, Wu, Kunyi, Cook, Christopher, Li, Liang, Wang, Zhao, Gu, Hanjiang, Lu, Mei, Hu, Guanglei, Ren, Kaixuan, Hu, Gang, Zeng, Weihui, Xia, Yumin, Liu, Yale
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2024
• Subjects: apoptosis; Desmoglein; Naloxone; Pemphigus vulgaris; STAT1; TWEAK; Pemphigus vulgaris; Desmoglein; apoptosis; Naloxone; TWEAK; STAT1
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2024.103307

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. Overview of the effect of opioid receptor antagonist on mitigating Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis. Anti-Dsg1/3 antibodies collected from pemphigus serum samples by affinity chromatography were administrated in HaCaT cells, HEK cells and neonatal mice respectively in vitro and in vivo. Pemphigus antibodies can increase the expression of TWEAK, which further triggers caspase activation via activating STAT1 signaling pathway. Ultimately, activated caspase3 acts on desmogleins, leading to down-regulation of desmoglein expression, apoptosis and acantholysis. The opioid receptor antagonist naloxone reverse TWEAK-induced pro-apoptotic effect in the early stages of signaling pathway activation, thereby protect keratinocytes intercellular adhesion. [Display omitted] •Our study is first to uncover a pathway through which tumor necrosis factor-like weak inducer of apoptosis (TWEAK) triggers apoptosis in keratinocytes, culminating in the depletion of desmoglein 1 and 3 (Dsg1/3) and subsequent acantholysis.•By delving into the downstream signaling cascades, we pinpoint caspase-3 as a pivotal player responsible for the breakdown of Dsg1/3 following TWEAK stimulation.•Our research illustrates that naloxone, an opioid receptor antagonist, displays compelling efficacy in attenuating TWEAK-induced apoptosis and reversing the loss of Dsg1/3 in keratinocytes.•Through both in vitro and in vivo investigations, we showcase the anti-apoptotic capabilities of naloxone and its exciting potential as a therapeutic intervention for pemphigus.