Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
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DOI：
10.1016/j.cmet.2006.05.011
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发表时间：
2006-07-01
期刊：
影响因子：
29
通讯作者：
Chawla, Ajay
中科院分区：
文献类型：
--
作者：
Vats, Divya;Mukundan, Lata;Chawla, Ajay
辅助性T细胞(Th)和巨噬细胞之间复杂的相互作用促进了动脉粥样硬化斑块的形成和发展。Th1细胞因子促进病变巨噬细胞的炎症激活，Th2细胞因子减轻巨噬细胞介导的炎症反应，增强其修复功能。尽管Th2细胞因子在生物学上具有重要意义，但Th2细胞因子如何促进抗炎巨噬细胞成熟的生化和分子基础尚不清楚。我们发现，在白介素4(IL-4)的作用下，信号转导和转录激活子6(STAT6)和PPARγ-辅活化子-1β(PGC-1β)诱导巨噬细胞脂肪酸氧化和线粒体生物发生程序。PGC-1β的转基因表达启动了巨噬细胞的交替激活并强烈抑制了促炎细胞因子的产生，而氧化代谢的抑制或RNAi介导的PGC-1β的敲除则减弱了这种免疫反应。这些数据阐明了线粒体氧化代谢与巨噬细胞激活的抗炎程序直接联系的分子途径，表明代谢疗法在治疗动脉粥样硬化性炎症方面具有潜在的作用。
Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPAR gamma-coactivator-1 beta (PGC-1 beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1 beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1 beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the antiinflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.