A Novel Regulator of Macrophage Activation: miR-223 in Obesity Associated Adipose Tissue Inflammation
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. Upon various types of stimuli, macrophages respond with either classical (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 window 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 and its role in controlling macrophage functions in adipose tissue inflammation and systemic insulin resistance. miR-223-/-mice on HFD exhibited an increased severity of systemic insulin resistance compared to wild-type mice, and this 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 (BMDM) we demonstrated that miR-223 is a novel regulator of macrophage polarization, which suppresses classic pro-inflammatory pathways and enhances the alternative anti-inflammatory responses. In addition, we identified Pknox1 is a genuine miR-223 target gene and an essential regulators for macrophage polarization.
Conclusions—For the first time, this study demonstrates that miR-223 acts to inhibit Pknox1, suppressing pro-inflammatory 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.
- Received December 16, 2011.
- Accepted April 10, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited