Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis
Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis
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DOI：
10.1038/s41467-020-16092-0
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发表时间：
2020-05-12
影响因子：
16.6
通讯作者：
Popov, Yury, V
中科院分区：
文献类型：
--
作者：
An, Ping;Wei, Lin-Lin;Popov, Yury, V
由于它们的细菌祖先，线粒体的许多组分与细菌具有结构相似性。从受损细胞线粒体释放分子危险信号（线粒体衍生的损伤相关分子模式，mito-DAMP）触发了强有力的炎症反应，但它们在纤维化中的作用尚不清楚。使用肝纤维化抵抗/易感小鼠品系系统，我们证明了从损伤的肝细胞线粒体（以mtDNA为主要活性组分）释放的mito-DAMPs直接激活肝星状细胞（肝中的纤维化细胞）并驱动肝瘢痕形成。线粒体DAMP的释放受吞噬驻留肝巨噬细胞和浸润Gr-1（+）髓样细胞对垂死肝细胞的吞噬作用控制。在患有非酒精性脂肪性肝炎（NASH）和显著肝纤维化的人类患者中，循环线粒体-DAMP显著增加。我们的研究确定了驱动肝纤维化的特定途径，具有重要的诊断和治疗意义。靶向从肝细胞释放线粒体-DAMP和/或调节巨噬细胞的吞噬功能代表了有希望的抗纤维化策略。进行性纤维化是许多慢性肝病发病率和死亡率的驱动因素，但其潜在机制尚未完全了解。在这里，作者表明线粒体衍生的损伤相关分子模式从受损的肝细胞中释放出来，并可以引发肝星状细胞的纤维化激活。
Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy. Progressive fibrosis is a driver of morbidity and mortality in many chronic liver diseases, but the underlying mechanisms are incompletely understood. Here, the authors show that mitochondria-derived damage-associated molecular patterns are released from injured hepatocytes and can trigger fibrogenic activation of hepatic stellate cells.