Inhibition of Caspase-1 Suppresses GSDMD-mediated Peritoneal Mesothelial Cell Pyroptosis and Inflammation in Peritoneal Fibrosis

Abstract

Pyroptosis, belonging to programmed cell death, is shown to be mediated by gasdermin D (GSDMD) and gains more and more attention in innate immunity and multiple diseases. However, the role of GSDMD-mediated pyroptosis in peritoneal fibrosis (PF) remains unclear. This study observed NLRP3 inflammasome activation and pyroptosis in the peritoneum of long-term peritoneal dialysis (PD) patients with PF. Moreover, it is found that high glucose (HG) can induce the activation of NLRP3 inflammasome by regulating TLR4/NF-κB and JNK/p38 MAPK signaling in human peritoneal mesothelial cells (HPMCs), leading to subsequent Caspase-1 activation. The cleaved Caspase-1 promoted pyroptosis-related transmembrane pore formation through activating GSDMD-N, and stimulated the HPMCs to secrete inflammatory factors including IL-1β and IL-18. GSDMD global deletion or pharmacologic pretreatment with Caspase-1 specific inhibitor VX-765 effectively inhibited the pyroptosis and inflammation, thereby ameliorating PF. Additionally, treatment with VX-765 and transfected with Caspase-1 siRNA or GSDMD siRNA also inhibited the transmembrane pore formation and inflammatory factors secretion in HG-induced HPMCs. Consistent with these results, delayed treatment with VX-765 also alleviated PF, indicating the therapeutic effect of VX-765. Taken together, the results demonstrate that pyroptosis may be a novel therapeutic target for peritoneal fibrosis.