Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition
Mitochondrial ROS-induced lysosomal dysfunction impairs autophagic flux and contributes to M1 macrophage polarization in a diabetic condition
复制标题
线粒体 ROS 诱导的溶酶体功能障碍会损害自噬通量并导致糖尿病患者中 M1 巨噬细胞极化
DOI：
10.1042/cs20190672
复制
发表时间：
2019-08-15
期刊：
影响因子：
6
通讯作者：
Lu，Yanrong
中科院分区：
文献类型：
--
作者：
Yuan，Yujia;Chen，Younan;Lu，Yanrong
巨噬细胞向M1表型极化及其随后的炎症反应与糖尿病并发症的进展有关。尽管自噬损伤对巨噬细胞炎症的不良后果，但高血糖条件下巨噬细胞自噬的调节尚不完全清楚。在这里，我们报告，自噬溶酶体系统和线粒体功能受损链脲佐菌素（STZ）诱导的糖尿病小鼠和高糖（HG）刺激的RAW 264.7细胞。线粒体功能障碍促进活性氧（ROS）的产生，并通过损害高血糖条件下巨噬细胞中溶酶体功能来阻断自噬通量。相反，Mito-TEMPO对线粒体ROS的抑制阻止了HG诱导的M1巨噬细胞极化，其作用通过阻断自噬通量而抵消。线粒体ROS在溶酶体功能障碍和M1巨噬细胞极化中的作用也在通过沉默NADH：泛醌氧化还原酶亚基-S4（Ndufs 4）诱导的线粒体复合物I缺陷RAW 264.7细胞中得到证实。这些发现证明线粒体ROS通过损害自噬-溶酶体系统在促进巨噬细胞向炎症表型极化中起关键作用，这可能为糖尿病并发症的新治疗提供线索。
Macrophage polarization toward the M1 phenotype and its subsequent inflammatory response have been implicated in the progression of diabetic complications. Despite adverse consequences of autophagy impairment on macrophage inflammation, the regulation of macrophage autophagy under hyperglycemic conditions is incompletely understood. Here, we report that the autophagy–lysosome system and mitochondrial function are impaired in streptozotocin (STZ)-induced diabetic mice and high glucose (HG)-stimulated RAW 264.7 cells. Mitochondrial dysfunction promotes reactive oxygen species (ROS) production and blocks autophagic flux by impairing lysosome function in macrophages under hyperglycemic conditions. Conversely, inhibition of mitochondrial ROS by Mito-TEMPO prevents HG-induced M1 macrophage polarization, and its effect is offset by blocking autophagic flux. The role of mitochondrial ROS in lysosome dysfunction and M1 macrophage polarization is also demonstrated in mitochondrial complex I defective RAW 264.7 cells induced by silencing NADH:ubiquinone oxidoreductase subunit-S4 (Ndufs4). These findings prove that mitochondrial ROS plays a key role in promoting macrophage polarization to inflammatory phenotype by impairing autophagy–lysosome system, which might provide clue to a novel treatment for diabetic complications.