A novel mechanism for NLRP3 inflammasome activation.
A novel mechanism for NLRP3 inflammasome activation.
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DOI：
10.1016/j.metop.2022.100166
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Zhang T;Zhao J;Liu T;Cheng W;Wang Y;Ding S;Wang R
NLRP3炎性小体作为先天免疫系统的重要组成部分，在各种代谢紊乱中发挥着重要作用。据报道，NLRP3炎性小体可被多种不同的刺激激活，如K+外排、线粒体功能障碍、溶酶体破坏和反式高尔基体解体等。然而，NLRP3炎性小体的激活至今尚无完善的模型，尤其是线粒体在NLRP3炎性小体激活中的潜在机制尚不清楚。鉴于在大多数先前的研究中，K+外排被广泛认为是触发NLRP3炎症小体激活的关系，我们试图阐明线粒体在K+外排诱导的NLRP3炎症小体激活中的作用。在这里，我们证明了LPS的炎症激活激活了参与线粒体生物发生和线粒体自噬的基因的表达，随后线粒体质量和线粒体膜电位也升高，表明线粒体在炎症反应中的作用。此外，我们通过沉默Tfam来抑制线粒体生物发生，Tfam的基因消融可以通过释放线粒体DNA （mtDNA）来消除K+外排诱导的NLRP3炎性体激活，因为通过EtBr治疗剥夺细胞mtDNA可以逆转K+外排诱导的炎性体激活。总之，我们揭示了巨噬细胞中K+外排诱导的mtDNA释放激活NLRP3炎症小体，并提出线粒体可能作为NLRP3炎症小体相关疾病的潜在治疗靶点。
The NLRP3 inflammasome, as an important component of the innate immune system, plays vital roles in various metabolic disorders. It has been reported that the NLRP3 inflammasome can be activated by a broad range of distinct stimuli, such as K+ efflux, mitochondrial dysfunction, lysosomal disruption and trans-Golgi disassembly, etc. However, there has been no well-established model for NLRP3 inflammasome activation so far, especially the underlying mechanisms for mitochondria in NLRP3 inflammasome activation remain elusive. Given that K+ efflux is a widely accepted nexus for triggering activation of NLRP3 inflammasome in most previous studies, we sought to elucidate the role of mitochondria in K+ efflux-induced NLRP3 inflammasome activation. Here, we demonstrated that inflammation activation by LPS evoked the expression of genes that involved in mitochondrial biogenesis and mitophagy, subsequently mitochondrial mass and mitochondrial membrane potential were also elevated, suggesting the contribution of mitochondria in inflammatory responses. Moreover, we inhibited mitochondrial biogenesis by silencing Tfam and genetic ablation of Tfam abolished the NLRP3 inflammasome activation induced by K+ efflux via release of mitochondrial DNA (mtDNA), as deprivation of cellular mtDNA by EtBr treatment could reverse inflammasome activation induced by K+ efflux. Collectively, we reveal that mtDNA release induced by K+ efflux in macrophages activates NLRP3 inflammasome, and propose that mitochondria may serve as a potential therapeutic target for NLRP3 inflammasome-related diseases.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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SFTSV 感染诱导 BAK/BAX 依赖性线粒体 DNA 释放以触发 NLRP3 炎症小体激活
影响因子：
8.8
作者：
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通讯作者：
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