T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response
T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response
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T 细胞 Ig Mucin-3 通过负向调节 TLR 反应促进脓毒症的稳态
DOI：
10.4049/jimmunol.1202661
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发表时间：
2013-03-01
影响因子：
4.4
通讯作者：
Han, Gencheng
中科院分区：
文献类型：
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作者：
Yang, Xiaomei;Jiang, Xingwei;Han, Gencheng
脓毒症是一种高度炎症状态，死亡率高，预测和治疗选择有限。在这项研究中，据我们所知，我们第一次发现T细胞Ig和粘蛋白结构域蛋白3(TIM-3)的下调和/或阻断与脓毒症的严重程度相关，这表明TIM-3在维持人和小鼠脓毒症模型的动态平衡中发挥着重要作用。阻断和/或下调TIM-3导致巨噬细胞活化增强，导致全身炎症反应，而巨噬细胞中TIM-3的过表达显著抑制TLR介导的促炎细胞因子的产生，表明TIM-3是TLR介导的免疫反应的负性调节因子。TIM-3和TLR4通路之间的串扰使TLR4成为TIM-3介导的先天性免疫反应负调控的重要贡献者。TIM-3信号通过增加PI3K-κ的磷酸化和A20的活性来抑制脂多糖-TLR4介导的NF-AkT B的激活。TIM-3的这种负调节作用反映了败血症患者的一种新的适应性代偿和保护机制，这一发现对调节这些患者的先天反应具有潜在的重要意义。
Sepsis is an excessive inflammatory condition with a high mortality rate and limited prediction and therapeutic options. In this study, for the first time, to our knowledge, we found that downregulation and/or blockade of T cell Ig and mucin domain protein 3 (Tim-3), a negative immune regulator, correlated with severity of sepsis, suggesting that Tim-3 plays important roles in maintaining the homeostasis of sepsis in both humans and a mouse model. Blockade and/or downregulation of Tim-3 led to increased macrophage activation, which contributed to the systemic inflammatory response in sepsis, whereas Tim-3 overexpression in macrophages significantly suppressed TLR-mediated proinflammatory cytokine production, indicating that Tim-3 is a negative regulator of TLR-mediated immune responses. Cross-talk between the Tim-3 and TLR4 pathways makes TLR4 an important contributor to Tim-3–mediated negative regulation of the innate immune response. Tim-3 signaling inhibited LPS–TLR4–mediated NF-κB activation by increasing PI3K–AKT phosphorylation and A20 activity. This negative regulatory role of Tim-3 reflects a new adaptive compensatory and protective mechanism in sepsis victims, a finding of potential importance for modulating innate responses in these patients.