Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis.
Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis.
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DOI：
10.1016/j.immuni.2016.01.001
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发表时间：
2016-03-15
期刊：
影响因子：
32.4
通讯作者：
Carter AB
中科院分区：
文献类型：
--
作者：
Larson-Casey JL;Deshane JS;Ryan AJ;Thannickal VJ;Carter AB
特发性肺纤维化（IPF）是一种发病率不断增加的破坏性肺部疾病。肺泡巨噬细胞线粒体氧化应激与肺纤维化直接相关。线粒体自噬是自噬体对功能障碍的线粒体的选择性吞噬，对细胞内稳态很重要，并且可以由线粒体氧化应激诱导。在这里，我们显示Akt 1诱导的巨噬细胞线粒体活性氧（ROS）和线粒体自噬。在巨噬细胞（Akt 1 −/− Lyz 2-cre）中携带Akt 1条件性缺失的小鼠和Park 2 −/−小鼠的线粒体自噬受损，活性转化生长因子-β1（TGF-β1）减少。尽管Akt 1增加TGF-β1的表达，但在Akt 1过表达的巨噬细胞中，线粒体自噬抑制消除了TGF-β1的表达和成纤维细胞分化。重要的是，条件性Akt 1 −/− Lyz 2-cre小鼠和Park 2 −/−小鼠的巨噬细胞凋亡增加，并免受肺纤维化的影响。此外，IPF肺泡巨噬细胞有证据表明线粒体自噬增加并显示凋亡抵抗。这些观察结果表明，Akt 1介导的线粒体自噬有助于肺泡巨噬细胞凋亡抵抗，是肺纤维化发展所必需的。
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder with increasing incidence. Mitochondrial oxidative stress in alveolar macrophages is directly linked to pulmonary fibrosis. Mitophagy, the selective engulfment of dysfunctional mitochondria by autophagasomes, is important for cellular homeostasis and can be induced by mitochondrial oxidative stress. Here, we show Akt1 induced macrophage mitochondrial reactive oxygen species (ROS) and mitophagy. Mice harboring a conditional deletion of Akt1 in macrophages (Akt1−/−Lyz2-cre) and Park2−/− mice had impaired mitophagy and reduced active transforming growth factor-β1 (TGF-β1). Although Akt1 increased TGF-β1 expression, mitophagy inhibition in Akt1-overexpressing macrophages abrogated TGF-β1 expression and fibroblast differentiation. Importantly, conditional Akt1−/− Lyz2-cre mice and Park2−/− mice had increased macrophage apoptosis and were protected from pulmonary fibrosis. Moreover, IPF alveolar macrophages had evidence of increased mitophagy and display apoptosis resistance. These observations suggest that Akt1-mediated mitophagy contributes to alveolar macrophage apoptosis resistance and is required for pulmonary fibrosis development.