Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA.
Antagonism of the STING Pathway via Activation of the AIM2 Inflammasome by Intracellular DNA.
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DOI：
10.4049/jimmunol.1502538
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Gajewski TF
中科院分区：
文献类型：
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作者：
Corrales L;Woo SR;Williams JB;McWhirter SM;Dubensky TW Jr;Gajewski TF
最近的证据表明，通过宿主STING途径对树突状细胞胞质DNA的先天免疫感知是导致自发T细胞对肿瘤反应的主要机制。然而，细胞内DNA触发的另一个主要途径AIM2炎性体对STING途径的功能输出的影响尚不清楚。我们发现，缺乏AIM2、ASC或caspase-1的树突状细胞和巨噬细胞对DNA产生明显更高的IFN-β。生化分析显示，炎症小体缺陷细胞中cGAMP、STING聚集、TBK1和IRF3磷酸化的产生增强。AIM2炎性小体诱导的焦亡是这种作用的主要组成部分，抑制caspase-1可减少细胞死亡，增加TBK1/IRF3的磷酸化和IFN-β的产生。我们的数据表明，体外激活小鼠巨噬细胞和树突状细胞中的AIM2炎性体可导致STING通路的激活降低，部分原因是通过促进caspase-1依赖性细胞死亡。
Recent evidence has indicated that innate immune sensing of cytosolic DNA in dendritic cells via the host STING pathway is a major mechanism leading to spontaneous T cell responses against tumors. However, the impact of the other major pathway triggered by intracellular DNA, the AIM2 inflammasome, on the functional output from the STING pathway is poorly understood. We found that dendritic cells and macrophages deficient in AIM2, ASC or caspase-1 produced markedly higher IFN-β in response to DNA. Biochemical analyses showed enhanced generation of cGAMP, STING aggregation, and TBK1 and IRF3 phosphorylation in inflammasome-deficient cells. Induction of pyroptosis by the AIM2 inflammasome was a major component of this effect, and inhibition of caspase-1 reduced cell death, augmenting phosphorylation of TBK1/IRF3 and production of IFN-β. Our data suggest that in vitro activation of the AIM2 inflammasome in murine macrophages and dendritic cells leads to reduced activation of the STING pathway, in part through promoting caspase-1-dependent cell death.