TREM2 Attenuates Microglial Pyroptosis in Sepsis-Associated Encephalopathy Through Modulation of the mtDNA-cGAS-STING Pathway.

Abstract

Microglial pyroptosis and the ensuing neuroinflammation are increasingly recognized as important contributors to sepsis-associated encephalopathy (SAE). Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in sepsis-related neuroinflammation and SAE; however, how TREM2 is linked to microglial pyroptosis remains incompletely understood. This study aimed to investigate the potential involvement of the mtDNA-cGAS-STING pathway in TREM2-associated regulation of microglial pyroptosis in SAE. An SAE mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS), and an in vitro microglial pyroptosis model was generated in BV2 cells using LPS/nigericin. TREM2 knockout led to more severe neuronal damage and cognitive impairment in LPS-challenged mice. In vivo, TREM2 deficiency was associated with enhanced hippocampal microglial pyroptosis and inflammatory cytokine release, and TREM2 knockdown promoted pyroptosis and inflammatory responses in BV2 microglial cells in vitro. Mechanistically, our in vitro data suggest that TREM2 helps maintain mitochondrial homeostasis, reduces the accumulation of mitochondrial DNA (mtDNA) in the cytosol, and suppresses activation of the cGAS-STING pathway. Depletion of mtDNA with ethidium bromide (EtBr) partially reversed TREM2 knockdown-induced cGAS-STING overactivation, reduced pyroptosis and inflammatory cytokine release, and alleviated microglia-associated neuronal injury. Together, these findings suggest that TREM2 is associated with reduced microglial pyroptosis and microglia-associated neuronal injury in SAE, and that mtDNA-cGAS-STING signaling may participate in this process.