GAS6/AXL signaling promotes M2 microglia efferocytosis to alleviate neuroinflammation in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a severe complication marked by acute central nervous system (CNS) injury and neuroinflammation. M2 microglia efferocytosis is essential for resolving neuroinflammation, but its regulatory mechanisms remain unclear. This study explored the GAS6/AXL signaling pathway in SAE, hypothesizing its role in enhancing anti-inflammatory responses and efferocytosis. A mouse model of SAE was established via cecal ligation and puncture (CLP), and cognitive impairments were assessed through behavioral tests. Brain tissues and microglia were isolated for RNA sequencing (RNA-Seq) to identify genes associated with the GAS6/AXL pathway. Recombinant GAS6 (rGAS6) protein and an AXL inhibitor were used to examine the pathway's effects on microglial Rac1 activity and functionality. Results demonstrated that GAS6/AXL activation significantly upregulated anti-inflammatory cytokines, enhanced efferocytosis, and suppressed pro-inflammatory responses, improving cognitive outcomes. These findings highlight GAS6/AXL as a critical modulator of microglial functions, providing a promising molecular target for treating SAE. GAS6/AXL Pathway Reduces Neuroinflammation in SAE via Regulation of Anti-Inflammatory and Efferocytic Function in M2 Microglia.