IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation
IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation
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DOI：
10.1016/j.immuni.2021.09.010
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发表时间：
2021-11-09
期刊：
影响因子：
32.4
通讯作者：
Kroenke, Gerhard
中科院分区：
文献类型：
--
作者：
Faas, Maria;Ipseiz, Natacha;Kroenke, Gerhard
选择性激活的巨噬细胞（AAM）有助于炎症的消退和组织修复。然而，控制其分化的分子途径仍未完全了解。在这里，我们发现解偶联蛋白 2 介导的线粒体重编程和转录因子 GATA3 特异性控制促解析 AAM 的分化，以响应警报蛋白 IL-33。在巨噬细胞中，IL-33 依次触发促炎基因的早期表达以及随后分化为 AAM。对潜在信号事件的整体分析表明，IL-33 诱导巨噬细胞快速代谢重连，涉及呼吸链解偶联和代谢物衣康酸产量增加，随后触发 GATA3 介导的 AAM 极化。单核吞噬细胞中 GATA3 的条件性缺失相应地消除了 IL-33 诱导的 AAM 分化和肌肉损伤时的组织修复。因此，我们的数据确定了单核吞噬细胞中不依赖于 IL-4 且依赖于 GATA3 的途径，该途径是由线粒体重新布线产生的，并控制着巨噬细胞的可塑性和炎症的消退。
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.