Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-γ Immunity in Mycobacterial Infection.
Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-γ Immunity in Mycobacterial Infection.
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AIM2-ASC 信号的缺陷揭示了分枝杆菌感染中 I 型干扰素的 STING 驱动的过度反应和保护性 IFN-γ 免疫的相互抑制
DOI：
10.4049/jimmunol.1701177
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发表时间：
2018-02-01
期刊：
影响因子：
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通讯作者：
Sun B
中科院分区：
文献类型：
--
作者：
Yan S;Shen H;Lian Q;Jin W;Zhang R;Lin X;Gu W;Sun X;Meng G;Tian Z;Chen ZW;Sun B
结核分枝杆菌的核酸可以通过细胞内DNA传感器检测，例如环GMP-AMP合酶和黑素瘤2（AIM 2）中的缺失，其导致I型IFN和促炎细胞因子IL-1β的释放。然而，在M.结核病体内感染尚不清楚。在这篇文章中，我们证明了AIM 2 −/−小鼠的分枝杆菌感染可诱导过度反应性IFN-γ和抑制性IFN-γ反应，导致更高的感染负担和更严重的病理学。我们还描述了潜在的机制，即激活的阿尔茨海默病相关的斑点样蛋白与一个关键的适配器，被称为刺激因子的IFN基因（STING），并抑制STING和下游TANK结合激酶1在骨髓来源的巨噬细胞和骨髓来源的树突状细胞之间的相互作用，从而减少I型IFN的诱导。值得注意的是，结核病相关斑点样蛋白表达与来自结核病患者的PBMC中的IFN-β水平呈负相关。这些数据表明，AIM 2-IL-1β信号传导途径通过阻碍STING和TANK结合激酶1之间的结合来负调节STING-I型IFN信号传导途径，所述TANK结合激酶1保护宿主免受M.肺结核感染。这一发现具有潜在的临床意义。免疫学杂志，2018，200：1016-1026。
The nucleic acids of Mycobacterium tuberculosis can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL-1β. However, whether cross-talk occurs between AIM2–IL-1β and cyclic GMP-AMP synthase–type I IFN signaling upon M. tuberculosis infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2−/− mice reciprocally induces overreactive IFN-γ and depressive IFN-γ responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck-like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow–derived macrophages and bone marrow–derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis-associated speck-like protein expression is inversely correlated with IFN-β levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2–IL-1β signaling pathway negatively regulates the STING–type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from M. tuberculosis infection. This finding has potential clinical significance. The Journal of Immunology, 2018, 200: 1016–1026.
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影响因子：
--
作者：
Liu C;Yue R;Yang Y;Cui Y;Yang L;Zhao D;Zhou X
通讯作者：
Zhou X
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
15.9
作者：
Antonelli, Lis R. V.;Rothfuchs, Antonio Gigliotti;Sher, Alan
通讯作者：
Sher, Alan
DOI：
10.4049/jimmunol.1502538
发表时间：
2016-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Corrales L;Woo SR;Williams JB;McWhirter SM;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF