Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.
Tim-3 inhibits macrophage control of Listeria monocytogenes by inhibiting Nrf2.
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Tim-3 通过抑制 Nrf2 来抑制巨噬细胞对单核细胞增生李斯特氏菌的控制。
DOI：
10.1038/srep42095
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Han G
中科院分区：
文献类型：
--
作者：
Wang Z;Sun D;Chen G;Li G;Dou S;Wang R;Xiao H;Hou C;Li Y;Feng J;Shen B;Han G
T细胞免疫球蛋白粘蛋白-3（Tim-3）是一种免疫检查点抑制剂，其调节异常与T细胞耐受和许多免疫疾病（如肿瘤和感染耐受）有关。然而，Tim-3在先天免疫中的生理病理学作用仍然难以捉摸。在这里，我们证明Tim-3抑制巨噬细胞吞噬L。通过抑制核红细胞2相关因子2（Nrf 2）信号通路，单核细胞生成增加细菌负荷。Tim-3信号通过增加其泛素化促进Nrf 2降解，从而减少其核转位。Tim-3-Nrf 2信号转导轴的下游分子CD 36和血红素加氧酶-1（HO-1）参与了Tim-3介导的L.单核细胞生成素在体外和体内均存在。我们在这里确定了Tim-3诱导感染耐受的新机制。通过调节Tim-3通路，我们证明了操纵巨噬细胞功能作为治疗感染性疾病（如李斯特菌感染）的有效工具的可行性。
T cell immunoglobulin mucin-3 (Tim-3) is an immune checkpoint inhibitor and its dysregulation has been related to T cell tolerance and many immune disorders, such as tumors and infection tolerance. However, the physiopathology roles of Tim-3 in innate immunity remain elusive. Here, we demonstrate that Tim-3 inhibits macrophage phagocytosis ofL. monocytogenesby inhibiting the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway and increases bacterial burden. Tim-3 signaling promotes Nrf2 degradation by increasing its ubiquitination and, as a result, decreasing its nuclear translocation. CD36 and heme oxygenase-1 (HO-1), two downstream molecules in the Tim-3-Nrf2 signaling axis, are involved in the Tim-3- mediated immune evasion ofL. monocytogenesbothin vitroandin vivo. We here identified new mechanisms by which Tim-3 induces infection tolerance. By modulating the Tim-3 pathway, we demonstrate the feasibility of manipulating macrophage function as a potent tool for treating infectious diseases, such as Listeria infection.