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A Novel Regulator of Macrophage Activation

2012; Lippincott Williams & Wilkins; Volume: 125; Issue: 23 Linguagem: Inglês

10.1161/circulationaha.111.087817

1524-4539

Guoqing Zhuang, Cong Meng, Xin Guo, Patali S. Cheruku, Lei Shi, Hang Xu, Honggui Li, Gang Wang, Ashley R. Evans, Stephen Safe, Chaodong Wu, Beiyan Zhou,

MicroRNA in disease regulation

Background— Macrophage activation plays a crucial role in regulating adipose tissue inflammation and is a major contributor to the pathogenesis of obesity-associated cardiovascular diseases. On various types of stimuli, macrophages respond with either classic (M1) or alternative (M2) activation. M1- and M2-mediated signaling pathways and corresponding cytokine production profiles are not completely understood. The discovery of microRNAs provides a new opportunity to understand this complicated but crucial network for macrophage activation and adipose tissue function. Methods and Results— We have examined the activity of microRNA-223 (miR-223) and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulin resistance. miR-223 −/− mice on a high-fat diet exhibited an increased severity of systemic insulin resistance compared with wild-type mice that was accompanied by a marked increase in adipose tissue inflammation. The specific regulatory effects of miR-223 in myeloid cell–mediated regulation of adipose tissue inflammation and insulin resistance were then confirmed by transplantation analysis. Moreover, using bone marrow–derived macrophages, we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic proinflammatory pathways and enhances the alternative antiinflammatory responses. In addition, we identified Pknox1 as a genuine miR-223 target gene and an essential regulator for macrophage polarization. Conclusion— For the first time, this study demonstrates that miR-223 acts to inhibit Pknox1, suppressing proinflammatory activation of macrophages; thus, it is a crucial regulator of macrophage polarization and protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance.