Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis.
Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis.
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线粒体 DNA 的胞浆逃逸触发 cGAS-STING-NLRP3 轴依赖性髓核细胞焦亡。
DOI：
10.1038/s12276-022-00729-9
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发表时间：
2022-03
影响因子：
12.8
通讯作者：
Yang C
中科院分区：
文献类型：
--
作者：
Zhang W;Li G;Luo R;Lei J;Song Y;Wang B;Ma L;Liao Z;Ke W;Liu H;Hua W;Zhao K;Feng X;Wu X;Zhang Y;Wang K;Yang C
下背痛（LBP）是一种主要的肌肉骨骼疾病和社会经济问题，患病率很高，主要涉及椎间盘（IVD）退变，其特征在于进行性髓核（NP）细胞死亡和NP组织中炎症微环境的发展。过量积累的细胞溶质DNA作为损伤相关分子模式（DAMP），其由cGAS-STING轴监测以触发许多退行性疾病中的免疫应答。NLRP 3炎性小体依赖性焦亡是一种促进慢性炎症反应和组织变性的炎性程序性死亡。然而，cGAS-STING轴和NLRP 3炎性小体诱导的焦亡在IVD变性发病机制中的关系仍不清楚。在这里，我们使用磁共振成像（MRI）和组织病理学来证明cGAS、STING和NLRP 3与IVD变性程度相关。在人NP细胞中，氧化应激以STING依赖性方式诱导cGAS-STING轴活化和NLRP 3炎性小体介导的焦亡。有趣的是，典型的形态和功能特征的线粒体通透性转换孔（mPTP）开放的线粒体DNA（mtDNA）的胞质逃逸在氧化应激下观察到人NP细胞。此外，在大鼠椎间盘针刺模型中，给予mPTP和自身mtDNA胞浆渗漏的特异性药理学抑制剂有效地减少了NLRP 3炎性小体介导的热变性NP细胞死亡和体外微环境炎症以及退行性进展。总的来说，这些数据突出了cGAS-STING-NLRP 3轴和焦亡在IVD变性进展中的关键作用，并为椎间盘源性LBP提供了有希望的治疗方法。对椎间盘退变（IVD）机制的研究揭示了限制腰痛进展的潜在治疗方法。IVD涉及椎间盘内广泛的炎症和细胞死亡，但具体如何进展尚不清楚。中国武汉华中科技大学的Cao Yang、Kun Wang及其同事在患者样本和大鼠模型中研究了IVD。氧化应激引发线粒体DNA泄漏到椎间盘中心细胞的细胞液中。这激活了免疫反应途径，并促使炎症细胞因子的释放。该通路的激活程度与IVD严重程度直接相关，提供了一种监测病情的潜在方法。给大鼠施用药物以阻断线粒体DNA渗漏减缓了IVD进展。
Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with a high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death and the development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as a damage-associated molecular pattern (DAMP) that is monitored by the cGAS-STING axis to trigger the immune response in many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis is a type of inflammatory programmed death that promotes a chronic inflammatory response and tissue degeneration. However, the relationship between the cGAS-STING axis and NLRP3 inflammasome-induced pyroptosis in the pathogenesis of IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) and histopathology to demonstrate that cGAS, STING, and NLRP3 are associated with the degree of IVD degeneration. Oxidative stress induced cGAS-STING axis activation and NLRP3 inflammasome-mediated pyroptosis in a STING-dependent manner in human NP cells. Interestingly, the canonical morphological and functional characteristics of mitochondrial permeability transition pore (mPTP) opening with the cytosolic escape of mitochondrial DNA (mtDNA) were observed in human NP cells under oxidative stress. Furthermore, the administration of a specific pharmacological inhibitor of mPTP and self-mtDNA cytosolic leakage effectively reduced NLRP3 inflammasome-mediated pyroptotic NP cell death and microenvironmental inflammation in vitro and degenerative progression in a rat disc needle puncture model. Collectively, these data highlight the critical roles of the cGAS-STING-NLRP3 axis and pyroptosis in the progression of IVD degeneration and provide promising therapeutic approaches for discogenic LBP. An investigation of the mechanisms responsible for intervertebral disc degeneration (IVD) reveals a potential treatment to limit the progression of low back pain. IVD involves widespread inflammation and cell death inside discs, but exactly how the condition progresses is unclear. Cao Yang, Kun Wang and co-workers at Huazhong University of Science and Technology, Wuhan, China, investigated IVD in patient samples and rat models. Oxidative stress triggered leakage of mitochondrial DNA into cellular fluid in cells in the center of discs. This activated an immune response pathway and prompted the release of inflammatory cytokines. The degree of activation of this pathway is directly linked to IVD severity, providing a potential method of monitoring the condition. Administering a drug to rats to block mitochondrial DNA leakage slowed IVD progression.
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影响因子：
82.9
作者：
Kerur N;Fukuda S;Banerjee D;Kim Y;Fu D;Apicella I;Varshney A;Yasuma R;Fowler BJ;Baghdasaryan E;Marion KM;Huang X;Yasuma T;Hirano Y;Serbulea V;Ambati M;Ambati VL;Kajiwara Y;Ambati K;Hirahara S;Bastos-Carvalho A;Ogura Y;Terasaki H;Oshika T;Kim KB;Hinton DR;Leitinger N;Cambier JC;Buxbaum JD;Kenney MC;Jazwinski SM;Nagai H;Hara I;West AP;Fitzgerald KA;Sadda SR;Gelfand BD;Ambati J
通讯作者：
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DOI：
10.1038/s41577-021-00524-z
发表时间：
2021-09
期刊：
Nature reviews. Immunology
影响因子：
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作者：
Decout A;Katz JD;Venkatraman S;Ablasser A
通讯作者：
Ablasser A
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影响因子：
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作者：
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DOI：
10.1002/advs.202002738
发表时间：
2021-03
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
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作者：
Bi X;Du C;Wang X;Wang XY;Han W;Wang Y;Qiao Y;Zhu Y;Ran L;Liu Y;Xiong J;Huang Y;Liu M;Liu C;Zeng C;Wang J;Yang K;Zhao J
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