Regulation of microglial phagocytosis and inflammatory gene expression by gas6 acting on the Axl/Mer family of tyrosine kinases
Regulation of microglial phagocytosis and inflammatory gene expression by gas6 acting on the Axl/Mer family of tyrosine kinases
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DOI：
10.1007/s11481-007-9090-2
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发表时间：
2008-06-01
影响因子：
6.2
通讯作者：
Landreth, Gary E.
中科院分区：
文献类型：
--
作者：
Grommes, Christian;Lee, C. Y. Daniel;Landreth, Gary E.
去除凋亡细胞是正常发育和组织维持的必要过程。重要的是，凋亡细胞刺激巨噬细胞的吞噬作用，同时积极抑制炎症反应。生长停滞特异性基因6（Gas 6）参与该过程，将凋亡细胞表面上的磷脂酰丝氨酸残基桥接至刺激吞噬作用的酪氨酸激酶的Axl/Mer家族。这些受体突变或缺失的动物表现出吞噬功能受损和免疫反应过度活跃的表型。我们报告Gas 6通过一种新的非经典吞噬机制诱导小胶质细胞的吞噬作用。Gas 6刺激II型相关的吞噬反应，但需要Vav磷酸化和Rac激活，将其与经典的II型机制区分开来。重要的是，Gas 6抑制脂多糖诱导的炎症分子IL-1 β和iNOS的表达。Gas 6通过抑制启动子活性抑制iNOS表达。目前的数据提供了直接的证据，Gas 6受体介导的抗炎反应的配体上发现的凋亡细胞的吞噬作用的同时刺激的作用。这些数据为在缺乏Axl/Mer受体的动物中观察到的表型提供了机制解释。
Removal of apoptotic cells is an essential process for normal development and tissue maintenance. Importantly, apoptotic cells stimulate their phagocytosis by macrophages while actively suppressing inflammatory responses. Growth arrest specific gene 6 (Gas6) is involved in this process, bridging phosphatidylserine residues on the surface of apoptotic cells to the Axl/Mer family of tyrosine kinases which stimulate phagocytosis. Animals with mutations or loss of these receptors exhibit phenotypes reflective of impaired phagocytosis and a hyperactive immune response. We report that Gas6 induces phagocytosis in microglia through a novel non-classical phagocytic mechanism. Gas6 stimulates a type-II-related phagocytic response, but requires Vav phosphorylation and Rac activation, distinguishing it from the classical type II mechanism. Importantly, Gas6 suppressed lipopolysaccharide-induced expression of the inflammatory molecules IL-1 beta and iNOS. Gas6 inhibited iNOS expression through suppression of promoter activity. The present data provide direct evidence for the role of Gas6 receptors in mediating an anti-inflammatory response to ligands found on apoptotic cells with the simultaneous stimulation of phagocytosis. These data provide a mechanistic explanation for the phenotype observed in animals lacking Axl/Mer receptors.