LB1800 TWEAK-induced apoptosis depletes desmoglein 1 and 3 via STAT1 in pemphigus

Purpose of the study: To investigate the role of TWEAK in manipulating keratinocyte apoptosis and its subsequent effects on the expression of Dsg1 and Dsg3 in the pathogenesis of pemphigus. Abstract: Pemphigus is a life-threatening autoimmune skin disease characterized by a loss of epidermal keratinocyte adhesion associated with depletion of desmoglein (Dsg) 1 and 3. Previously, we elucidated that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) weakened cell adhesion via binding to fibroblast growth factor-inducible 14 (Fn14). Here, we further investigated the role of TWEAK in manipulating the expression of Dsg1 and Dsg3 in pemphigus. In the lesional and perilesional skin of pemphigus patients, overexpression of TWEAK (p=0.0181) and significant apoptosis (p<0.0001) were found concurrently. However, the expression of Dsg1 and Dsg3 decreased, which led us to speculate that TWEAK may promote keratinocyte apoptosis to deplete Dsg1 and Dsg3, therefore, participating in the pathogenesis of pemphigus. In vitro experiments showed that TWEAK-stimulated keratinocytes had increased apoptosis and decreased Dsg1 (p=0.0063) and Dsg3 (p=0.0368) expression, while Fn14 RNA interference reversed the effects, validating our speculation. Bulk-RNA sequencing and western blotting revealed that it was caspase-3 mediated the apoptosis and Dsg1/3 depletion after TWEAK stimuli, while the administration of caspase inhibitors Z-VAD and Boc-D further validated it. TWEAK-stimulated keratinocytes also exhibited STAT1 activation, which has been proven to promote TWEAK-induced apoptosis. In addition, apoptosis and Dsg1/3 reduction were efficiently blocked by STAT1 inhibitor Fludarabine. These data indicate that TWEAK may play an anti-adhesion role via apoptosis-induced Dsg1/3 depletion regulated by STAT1 phosphorylation. Thus, TWEAK may serve as a biomarker or therapeutic target for pemphigus.