Endothelial Piezo1 Mediates Barrier Dysfunction and NLRP3 Inflammasomes Activation in Psoriasis.

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by abnormal dilation of microvessels in the dermal papillary layer. Multiple studies have demonstrated that vascular endothelial cells regulate vascular function rather than merely acting as passive barriers. Piezo1 serves as a critical mechanical switch, sensing mechanical changes induced by vasodilation. However, the precise pathological role of Piezo1 in psoriasis remains unclear. In this study, we observed significant upregulation of Piezo1 in endothelial cells from the psoriatic dermis. Piezo1 activation impaired endothelial barrier function and promoted the expression of inflammatory factors. These alterations activated the NLRP3 inflammasome, which secretes IL-1β and IL-18, contributing to the local immune dysregulation characteristic of psoriasis. In addition, Piezo1 promoted mitochondrial ROS production and the release of mitochondrial DNA into the cytoplasm, thereby activating the NLRP3 inflammasome in endothelial cells. Furthermore, in mice with imiquimod-induced psoriasis-like dermatitis, Piezo1 suppression significantly alleviated the psoriasis-like phenotype, microvascular dilation, inflammatory infiltration, and NLRP3 inflammasome activation. Our findings suggest that the tortuous and dilated microvasculature in psoriatic skin disrupts vascular barriers and promotes NLRP3 inflammasome activation through Piezo1, contributing to the onset and progression of psoriasis.