Van den Bossche Jan, Baardman Jeroen, Otto Natasja A, van der Velden Saskia, Neele Annette E, van den Berg Susan M, Luque-Martin Rosario, Chen Hung-Jen, Boshuizen Marieke C S, Ahmed Mohamed, Hoeksema Marten A, de Vos Alex F, de Winther Menno P J
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
Cell Rep. 2016 Oct 11;17(3):684-696. doi: 10.1016/j.celrep.2016.09.008.
Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.
巨噬细胞是先天性免疫细胞，可根据其微环境采取多种激活状态。通过促进炎性（M1）巨噬细胞向抗炎（M2）巨噬细胞的重新极化来编辑巨噬细胞激活以减轻炎症性疾病引起了人们的高度关注。在这里，我们发现小鼠和人类的M1巨噬细胞在体外和体内暴露于IL-4后无法转化为M2细胞。与之形成鲜明对比的是，M2巨噬细胞更具可塑性，很容易重新极化到炎性M1状态。我们确定M1相关的线粒体氧化磷酸化抑制是阻止M1→M2重新极化的因素。抑制一氧化氮的产生，这是M1细胞中的关键效应分子，可减轻线粒体功能的下降，以改善向M2巨噬细胞的代谢和表型重编程。因此，炎性巨噬细胞激活会削弱氧化磷酸化，从而阻止重新极化。治疗性恢复线粒体功能可能有助于改善炎性巨噬细胞向抗炎细胞的重编程以控制疾病。
