Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation.
Microglial immunoreceptor tyrosine-based activation and inhibition motif signaling in neuroinflammation.
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DOI：
10.4061/2010/587463
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发表时间：
2010-06-22
影响因子：
--
通讯作者：
Neumann, Harald
中科院分区：
文献类型：
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作者：
Linnartz, Bettina;Wang, Yiner;Neumann, Harald
在没有炎症的情况下消除细胞外聚集物和凋亡神经膜对于脑组织稳态至关重要。在哺乳动物中枢神经系统中，该过程中的重要分子是 Fc 受体和 DAP12 相关受体，它们都会触发小胶质细胞免疫受体基于酪氨酸的激活基序 - (ITAM-) Syk 信号级联。髓系细胞上表达的小胶质细胞触发受体-2 (TREM2)、信号调节蛋白-β1 和补体受体-3 (CD11b/CD18) 通过衔接蛋白 DAP12 发出信号并激活小胶质细胞的吞噬活性。小胶质细胞 ITAM 信号受体受到免疫受体酪氨酸抑制基序 (ITIM) 信号分子（例如唾液酸结合免疫球蛋白超家族凝集素 (Siglecs)）的反向调节。 Siglecs 可以通过 ITIM 信号传导抑制小胶质细胞的促炎和吞噬活性。此外，Siglec-11 与神经元糖萼上唾液酸的相互作用可减轻小胶质细胞神经毒性。因此，ITAM 和 ITIM 信号受体在神经炎症过程中调节小胶质细胞的吞噬作用和细胞因子的表达。它们的功能障碍可能导致吞噬细胞清除受损和慢性炎症引发的神经变性。
Elimination of extracellular aggregates and apoptotic neural membranes without inflammation is crucial for brain tissue homeostasis. In the mammalian central nervous system, essential molecules in this process are the Fc receptors and the DAP12-associated receptors which both trigger the microglial immunoreceptor tyrosine-based activation motif- (ITAM-) Syk-signaling cascade. Microglial triggering receptor expressed on myeloid cells-2 (TREM2), signal regulatory protein-beta1, and complement receptor-3 (CD11b/CD18) signal via the adaptor protein DAP12 and activate phagocytic activity of microglia. Microglial ITAM-signaling receptors are counter-regulated by immunoreceptor tyrosine-based inhibition motif- (ITIM-) signaling molecules such as sialic acid-binding immunoglobulin superfamily lectins (Siglecs). Siglecs can suppress the proinflammatory and phagocytic activity of microglia via ITIM signaling. Moreover, microglial neurotoxicity is alleviated via interaction of Siglec-11 with sialic acids on the neuronal glycocalyx. Thus, ITAM- and ITIM-signaling receptors modulate microglial phagocytosis and cytokine expression during neuroinflammatory processes. Their dysfunction could lead to impaired phagocytic clearance and neurodegeneration triggered by chronic inflammation.