Kruppel-like factor 4 regulates macrophage polarization
Kruppel-like factor 4 regulates macrophage polarization
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DOI：
10.1172/jci45444
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发表时间：
2011-07-01
影响因子：
15.9
通讯作者：
Jain, Mukesh K.
中科院分区：
文献类型：
--
作者：
Liao, Xudong;Sharma, Nikunj;Jain, Mukesh K.
目前的范例表明，两个巨噬细胞亚群，称为M1和M2，参与炎症和宿主防御。虽然M1和M2巨噬细胞的不同功能已被深入研究-前者被认为是促炎性的，而后者则是炎性的-但它们物种形成的决定因素尚未完全了解。在这里，我们报告了我们的研究，确定Kruppel样因子4（ICLF 4）作为巨噬细胞极化的关键调节因子。在M2巨噬细胞中强烈诱导巨噬细胞KLF 4表达，在M1巨噬细胞中强烈降低，在体内人类炎症范例中重现了观察结果。在机制上，发现KLF 4与Stat 6合作诱导M2遗传程序，并通过隔离NF-κ B活化所需的共活化剂来抑制M1靶点。KLF 4缺陷型巨噬细胞表现出促炎基因表达增加、杀菌活性增强和代谢改变。此外，携带骨髓特异性ICLF 4缺失的小鼠表现出延迟的伤口愈合，并且易于发展饮食诱导的肥胖、葡萄糖耐受不良和胰岛素抵抗。总的来说，这些数据将KLF 4确定为我们认为是巨噬细胞极化的新型调节剂。
Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied - the former are considered proinflammatory and the latter antiinflammatory - the determinants of their speciation are incompletely understood. Here we report our studies that identify Kruppel-like factor 4 (ICLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-kappa B activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of ICLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization.