德国埃尔朗根-纽伦堡大学Gerhard Krönke团队发现，IL-33诱导的代谢重编程控制替代性活化巨噬细胞的分化和炎症的消退。该项研究成果于2021年10月12日在线发表在《免疫》杂志上。

研究人员表明，解偶联蛋白-2介导的线粒体重编程和转录因子GATA3特异性地在响应警报素IL-33时，促进了消炎的替代性活化巨噬细胞（AAM）的分化。在巨噬细胞中，IL-33依次触发了促炎症基因的早期表达和随后分化为AAM。对基本信号事件的全面分析显示，IL-33诱导了巨噬细胞的快速代谢重构，涉及呼吸链的解耦和代谢物衣康酸的增加，这随后引发了GATA3介导的AAM极化。

单核吞噬细胞中GATA3的条件性缺失相应地废除了IL-33诱导的AAM分化和肌肉损伤后的组织修复。因此，这些数据确定了单核吞噬细胞中一个不依赖IL-4和依赖GATA3的途径，这个途径来源于线粒体重塑并控制巨噬细胞的可塑性和炎症的缓解。

据介绍，AAM有助于解决炎症和组织修复。然而，指导它们分化的分子途径仍未完全了解。

附：英文原文

Title: IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation

Author: Maria Faas, Natacha Ipseiz, Jochen Ackermann, Stephan Culemann, Anika Grüneboom, Fenja Schrder, Tobias Rothe, Carina Scholtysek, Martin Eberhardt, Martin Bttcher, Philipp Kirchner, Cornelia Stoll, Arif Ekici, Maximilian Fuchs, Meik Kunz, Benno Weigmann, Stefan Wirtz, Roland Lang, Joerg Hofmann, Julio Vera, David Voehringer, Alessandro Michelucci, Dimitrios Mougiakakos, Stefan Uderhardt, Georg Schett, Gerhard Krnke

Issue&Volume: 2021-10-12

Abstract: Alternatively activated macrophages (AAMs) contribute to the resolution of inflammationand tissue repair. However, molecular pathways that govern their differentiation haveremained incompletely understood. Here, we show that uncoupling protein-2-mediatedmitochondrial reprogramming and the transcription factor GATA3 specifically controlledthe 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 subsequentdifferentiation into AAMs. Global analysis of underlying signaling events revealedthat IL-33 induced a rapid metabolic rewiring of macrophages that involved uncouplingof the respiratory chain and increased production of the metabolite itaconate, whichsubsequently triggered a GATA3-mediated AAM polarization. Conditional deletion ofGATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation ofAAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independentand GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrialrewiring and controls macrophage plasticity and the resolution of inflammation.

DOI: 10.1016/j.immuni.2021.09.010

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00395-2