Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy.
Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy.
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DOI：
10.4161/15548627.2014.981915
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发表时间：
2015
期刊：
影响因子：
13.3
通讯作者：
Evans TJ
中科院分区：
文献类型：
--
作者：
Jabir MS;Hopkins L;Ritchie ND;Ullah I;Bayes HK;Li D;Tourlomousis P;Lupton A;Puleston D;Simon AK;Bryant C;Evans TJ
核苷酸结合域、富含亮氨酸重复序列的家族半胱天冬酶募集域包含 4 (NLRC4) 炎性体可以通过微生物 III 型分泌装置 (T3SS) 的易位产物被病原菌激活。最近的研究表明，自噬下调了NLRP3炎症小体的激活，但自噬对NLRC4激活的影响尚不清楚。我们开始使用铜绿假单胞菌来确定自噬如何影响这一过程，该细菌通过其 T3SS 激活 NLRC4 炎症小体。感染导致 T3SS 依赖性线粒体损伤，活性氧中间体的产生增加和线粒体 DNA 的释放。抑制线粒体活性氧释放或降解细胞内线粒体 DNA 可消除 NLRC4 炎性体激活。此外，缺乏线粒体的巨噬细胞在感染后无法激活 NLRC4。通过自噬去除受损的线粒体可显着减弱 NLRC4 炎性体的激活。线粒体DNA与NLRC4免疫沉淀物特异性结合，转染线粒体DNA直接激活NLRC4炎症小体； DNA 的氧化增强了这种效果。在铜绿假单胞菌感染的体内模型中，自噬的操纵改变了炎症小体激活和炎症的程度。我们的结果揭示了一种新机制，通过线粒体损伤和由自噬下调的细菌 T3SS 触发的线粒体 DNA 释放，促进铜绿假单胞菌激活 NLRC4。
The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS-dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy.