Work

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

Year: 2024

Type: article

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. 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. • 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.

Source: Journal of Autoimmunity

DOI: 10.1016/j.jaut.2024.103307