Essential roles of S100A10 in Toll-like receptor signaling and immunity to infection.
Essential roles of S100A10 in Toll-like receptor signaling and immunity to infection.
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S100A10 在 Toll 样受体信号传导和感染免疫中的重要作用
DOI：
10.1038/s41423-019-0278-1
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发表时间：
2020-10
影响因子：
24.1
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Lou Y;Han M;Liu H;Niu Y;Liang Y;Guo J;Zhang W;Wang H
Toll样受体（TLRs）是关键的模式识别受体，介导对感染的先天免疫应答。然而，不受控制的TLR激活可导致严重的炎症性疾病，如败血症休克。TLR应答的调控分子机制尚未完全清楚。在此，我们证明了S100A10在TLR信号传导中的重要功能。S100A10在巨噬细胞中组成性表达，但在TLR激活时显著下调。S100A10缺陷型巨噬细胞对TLR刺激过度应答，并且S100A10缺陷型小鼠对内毒素诱导的致死性休克和大肠杆菌诱导的腹腔败血症更为敏感。从机制上讲，S100A10通过干扰受体近端信号成分的适当募集和激活来调节巨噬细胞的炎症反应，并最终抑制TLR触发的下游信号传导。这些发现拓展了我们对TLR信号传导的理解，并确立了S100A10作为TLR功能的关键负调控因子以及治疗炎症性疾病的潜在治疗靶点。
Toll-like receptors (TLRs) are key pattern recognition receptors that mediate innate immune responses to infection. However, uncontrolled TLR activation can lead to severe inflammatory disorders such as septic shock. The molecular mechanisms through which TLR responses are regulated are not fully understood. Here, we demonstrate an essential function of S100A10 in TLR signaling. S100A10 was constitutively expressed in macrophages, but was significantly downregulated upon TLR activation. S100A10-deficient macrophages were hyperresponsive to TLR stimulation, and S100A10-deficient mice were more sensitive to endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Mechanistically, S100A10 regulated macrophage inflammatory responses by interfering with the appropriate recruitment and activation of the receptor-proximal signaling components and eventually inhibited TLR-triggered downstream signaling. These findings expand our understanding of TLR signaling and establish S100A10 as an essential negative regulator of TLR function and a potential therapeutic target for treating inflammatory diseases.
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