Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA.
Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA.
Cell Metab. 2019 Feb 5;29(2):443-456.e5. doi: 10.1016/j.cmet.2018.12.004. Epub 2018 Dec 27.
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 of IL-10 transcription factor PBX1. Il-10 activation by the respiratory chain was also important in 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.
在伤口损伤过程中，吞噬作用会使巨噬细胞充满与吞噬细胞本身几乎相等的代谢物负荷。一个及时的问题涉及代谢吞噬信号如何调节标志性的抗炎巨噬细胞反应。在这里，我们报告了吞噬作用过程中激活的巨噬细胞的代谢组学，揭示了白细胞介素 10（IL-10）细胞因子的上升，这与糖酵解无关，但得到了凋亡细胞脂肪酸和线粒体β氧化、电子传递链和辅酶 NAD 的增强的支持。由于线粒体复合物 III 缺陷导致的 IL-10 丧失，通过添加 NAD 前体得到了显著的挽救。这激活了 SIRTUIN1 信号级联反应，在很大程度上独立于 ATP，最终导致 IL-10 转录因子 PBX1 的激活。呼吸链对 IL-10 的激活在体内也很重要，因为吞噬细胞线粒体功能障碍导致心肌损伤后的心脏破裂。这些发现强调了一个新的范例，即巨噬细胞利用吞噬作用的代谢物和电子传递来进行抗炎重编程，最终导致器官修复。
