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

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-06-06 DOI:10.1038/s41420-025-02507-8

Yuedong Tang, Hanbing Hu, Qiliang Xie, Jie Shen

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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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GAS6/AXL信号促进M2小胶质细胞efferocysis减轻败血症相关脑病的神经炎症。

脓毒症相关脑病（SAE）是一种以急性中枢神经系统（CNS）损伤和神经炎症为特征的严重并发症。M2小胶质细胞efferocytosis是解决神经炎症所必需的，但其调节机制尚不清楚。本研究探讨了SAE中GAS6/AXL信号通路，并推测其在增强抗炎反应和efferocytic中的作用。通过盲肠结扎穿刺（CLP）建立SAE小鼠模型，并通过行为测试评估认知障碍。分离脑组织和小胶质细胞进行RNA测序（RNA- seq），鉴定与GAS6/AXL通路相关的基因。利用重组GAS6 （rGAS6）蛋白和AXL抑制剂检测该通路对小胶质细胞Rac1活性和功能的影响。结果表明，激活GAS6/AXL可显著上调抗炎细胞因子，增强efferocytosis，抑制促炎反应，改善认知结果。这些发现强调了GAS6/AXL作为小胶质细胞功能的关键调节剂，为治疗SAE提供了一个有希望的分子靶点。GAS6/AXL通路通过调节M2小胶质细胞的抗炎和Efferocytic功能减少SAE的神经炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.