Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair.
Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair.
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DOI：
10.1016/j.cmet.2018.12.004
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发表时间：
2019-02
期刊：
影响因子：
29
通讯作者：
Shuang Zhang;S. Weinberg;Matthew DeBerge;Anastasiia Gainullina;M. Schipma;J. Kinchen;I. Ben-Sahra
中科院分区：
文献类型：
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作者：
Shuang Zhang;S. Weinberg;Matthew DeBerge;Anastasiia Gainullina;M. Schipma;J. Kinchen;I. Ben-Sahra
在创伤过程中，吞噬作用使巨噬细胞的代谢物负荷几乎等于吞噬细胞本身。一个及时的问题与代谢吞噬信号如何调节标志性抗炎巨噬细胞反应有关。在这里，我们报告了激活的巨噬细胞在吞噬过程中的代谢产物，揭示了白细胞介素10(IL-10)细胞因子的升高，这种细胞因子不依赖于糖酵解，但受到凋亡细胞脂肪酸和线粒体β氧化、电子传输链和辅酶NAD+升高的支持。加入NAD+前体可显著挽救线粒体复合体III缺陷引起的IL-10丢失。这激活了SIRTUIN1信号级联，在很大程度上不依赖于ATP，最终导致IL-10转录因子PBX1的激活。呼吸链激活IL-10在体内也是重要的，因为流出细胞线粒体功能障碍导致心肌损伤后心脏破裂。这些发现突显了一种新的范式，即巨噬细胞利用泡腾细胞代谢物和电子传输进行抗炎重新编程，最终导致器官修复。
During wound injury, efferocytosis fills the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to how metabolic phagocytic signaling regulates the signature anti-inflammatory macrophage response. Here we report the metabolome of activated macrophages during efferocytosis to reveal an interleukin-10 (IL-10) cytokine escalation that was independent of glycolysis yet bolstered by apoptotic cell fatty acids and mitochondrial β-oxidation, the electron transport chain, and heightened coenzyme NAD+. Loss of IL-10 due to mitochondrial complex III defects was remarkably rescued by adding NAD+precursors. This activated a SIRTUIN1 signaling cascade, largely independent of ATP, that culminated in activation ofIL-10transcription factor PBX1.Il-10activation by the respiratory chain was also importantin vivo, as efferocyte mitochondrial dysfunction led to cardiac rupture after myocardial injury. These findings highlight a new paradigm whereby macrophages leverage efferocytic metabolites and electron transport for anti-inflammatory reprogramming that culminates in organ repair.