745 Gasdermin a guards epidermal differentiation and cornification in skin barrier repair: Its role in atopic dermatitis pathogenesis

Atopic dermatitis (AD) is featured with impaired skin barrier. The stratum corneum (SC) and the intercellular tight junctions (TJs) constitute permeability barrier, which essential to protect host water loss pathogen entrance. SC constantly renewed by differentiating keratinocytes through cornification, during autophagy contributes organelles nucleus elimination. human GSDMA its mouse homologs Gsdma1–3 are expressed in suprabasal epidermis. Although a pyroptotic role for GSDMA/Gsdma1 defense against Streptococcus pyogenes has been reported, physiological function of Gsdma1/a2/a3 epidermal homeostasis remains elusive. Herein, repeated barrier disruption, we found that TJ formation maturation were defective Gsdma1/a3-deficient Using comparative gene profiling analysis, mitochondrial respiration measurement, vivo tracing turnover, our data indicate Gsdma1/a3 required acute cornification inducing dysfunction ensuing mitophagy. In MC903-induced AD-like animal model, demonstrated Gsdma1/a3-deficiency selectively enhanced Th2 response. Remarkably, expression reduced epidermis patients AD compared normal individuals. might be involved pathogenesis, likely GSDMA-mediated differentiation cornification.