2. Academic Validation
  3. GAS6/AXL signaling promotes M2 microglia efferocytosis to alleviate neuroinflammation in sepsis-associated encephalopathy

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

  • Cell Death Discov. 2025 Jun 6;11(1):268. doi: 10.1038/s41420-025-02507-8.
Yuedong Tang 1 2 3 4,  Hanbing Hu 1 2 3 4,  Qiliang Xie 1 2 3 4,  Jie Shen 5 6 7 8
Affiliations

Affiliations

  • 1 Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, 201508, China.
  • 2 Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China.
  • 3 Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, Shanghai, 201508, China.
  • 4 Jinshan Hospital of Fudan University, Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Shanghai, 201508, China.
  • 5 Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, 201508, China. j1999sh@126.com.
  • 6 Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China. j1999sh@126.com.
  • 7 Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, Shanghai, 201508, China. j1999sh@126.com.
  • 8 Jinshan Hospital of Fudan University, Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, Shanghai, 201508, China. j1999sh@126.com.
PMID: 40480981 DOI: 10.1038/s41420-025-02507-8
Abstract

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.

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