Rosiglitazone alleviates white matter injury by inhibiting NLRP3/capspase-1 mediated microglial pyroptosis via downregulating KLF4.

Abstract

White matter injury (WMI) is a critical pathological feature of various neurological disorders. Microglial pyroptosis, a form of inflammatory cell death mediated by the NLRP3/caspase-1 inflammasome, exacerbates neuroinflammation and contributes to WMI progression. This study investigated the therapeutic potential of rosiglitazone (ROSI), a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, in alleviating WMI by targeting microglial pyroptosis. In vitro, LPS/ATP-stimulated HMC3 cells exhibited elevated pyroptosis markers (NLRP3, caspase-1, GSDMD, ASC) and inflammatory cytokines (IL-1β, IL-18), which were significantly suppressed by ROSI. ROSI also reduced LPS/ATP-induced injury in co-cultured MO3.13 oligodendrocyte precursor cells (OPCs), improving cell viability and reducing apoptosis. In direct-treatment experiments, ROSI did not significantly affect MO3.13 cell viability, supporting an indirect protective effect on OPCs. Mechanistically, ROSI downregulated KLF4, a transcription factor critical for NLRP3 activation, and this effect was confirmed using KLF4-overexpressing HMC3 cells, where ROSI's anti-pyroptotic effects were abolished. Supplementary GW9662 experiments further suggested that the inhibitory effects of ROSI were not obviously reversed by PPAR-γ antagonism. In vivo, ROSI treatment in a rat model of WMI improved cognitive function, attenuated white matter pathology, and suppressed microglial pyroptosis by reducing NLRP3/caspase-1 activation and inflammatory cytokine release. Notably, ROSI downregulated KLF4 in microglia isolated from WMI rats, further supporting its role in inhibiting pyroptosis. Collectively, these findings demonstrated that ROSI alleviated WMI by inhibiting NLRP3/caspase-1-mediated microglial pyroptosis through downregulation of KLF4, highlighting its potential as a therapeutic strategy for WMI.