A Novel Regulator of Macrophage Activation: miR-223 in Obesity-Associated Adipose Tissue Inflammation

• Published in: Circulation (New York, N.Y.) N.Y.), 2012-06, Vol.125 (23), p.2892-2903
• Main Authors: GUOQING ZHUANG, CONG MENG, CHAODONG WU, BEIYAN ZHOU, XIN GUO, CHERUKU, Patali S, LEI SHI, HANG XU, HONGGUI LI, GANG WANG, EVANS, Ashley R, SAFE, Stephen
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - immunology; Adipose Tissue - cytology; Adipose Tissue - immunology; Animals; Biological and medical sciences; Blood and lymphatic vessels; Bone Marrow Transplantation; Cardiology. Vascular system; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Polarity - genetics; Cell Polarity - immunology; Cells, Cultured; Coculture Techniques; Coronary heart disease; Dietary Fats - pharmacology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Heart; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Homeodomain Proteins - metabolism; Immunophenotyping; Inflammation - immunology; Insulin Resistance - immunology; Macrophages - cytology; Macrophages - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; MicroRNAs - immunology; MicroRNAs - metabolism; Myeloid Cells - cytology; Myeloid Cells - immunology; Obesity - immunology; Predictive Value of Tests; RNA, Small Interfering - genetics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.111.087817

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. 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. 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.