Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.
Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.
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DOI：
10.1038/nature10992
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发表时间：
2012-05-10
期刊：
影响因子：
64.8
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
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作者：
Oka, Takafumi;Hikoso, Shungo;Yamaguchi, Osamu;Taneike, Manabu;Takeda, Toshihiro;Tamai, Takahito;Oyabu, Jota;Murakawa, Tomokazu;Nakayama, Hiroyuki;Nishida, Kazuhiko;Akira, Shizuo;Yamamoto, Akitsugu;Komuro, Issei;Otsu, Kinya
心力衰竭是工业化国家发病率和死亡率的主要原因。虽然在大多数情况下，微生物感染与心力衰竭的发展无关，但炎症与心力衰竭的发病机制有关。然而，负责在心脏内启动和整合炎症反应的机制仍然不清楚。线粒体是由细菌演化而来的内共生生物，含有与细菌相似的DNA。心肌细胞的自噬/溶酶体系统降解受外部血流动力学应激损伤的线粒体。在这里，我们发现从自噬细胞中逃逸的线粒体DNA自主地导致心肌细胞中toll样受体（TLR） 9介导的炎症反应，并能够诱导心肌炎和扩张型心肌病。在基线条件下，溶酶体脱氧核糖核酸酶（DNase） II的心脏特异性缺失没有显示出心脏表型，但增加了死亡率，并在压力过载治疗后10天引起严重的心肌炎和扩张性心肌病。在发病早期，DNase ii缺陷心脏表现为炎症细胞浸润，炎症细胞因子mRNA表达增加，心肌自溶酶体中线粒体DNA沉积积累。在DNA酶ii缺陷小鼠中，给予TLR9抑制寡脱氧核苷酸（已知可被细菌DNA激活）或消融TLR9可减轻心肌病的发展。此外，tlr9消融改善了压力过载引起的心功能障碍和炎症，即使在具有野生型Dnase2a等位基因的小鼠中也是如此。这些数据为心力衰竭慢性炎症的发生机制提供了新的视角。
Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA. Mitochondria damaged by external hemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes. Here, we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis, and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts exhibited infiltration of inflammatory cells and increased mRNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of the inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9-ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.
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影响因子：
15.9
作者：
Yamaguchi, O;Watanabe, T;Otsu, K
通讯作者：
Otsu, K
循环线粒体 DAMP 会引起对损伤的炎症反应。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
MEERSON, FZ;ZALETAYEVA, TA;PSHENNIKOVA, MG
通讯作者：
PSHENNIKOVA, MG
影响因子：
3.2
作者：
MOSGOLLER, W;SCHOFER, C;WACHTLER, F
通讯作者：
WACHTLER, F
影响因子：
--
作者：
Lu, ZH;Dono, K;Monden, M
通讯作者：
Monden, M