Abstract 17934: MicroRNA-223 Regulates Macrophage Polarization and Protects Mice from Diet-Induced Insulin Resistance and Adipose Tissue Inflammation
Macrophage-mediated adipose tissue inflammation is a crucial contributor to the risk of Cardiovascular disease (CVD) associated obesity. microRNAs are important regulators for various basic cell functions, such as proliferation, differentiation and apoptosis. We found that miR-223, a microRNA with high abundance in the bone marrow, can regulate adipose tissue inflammation by modulating macrophage polarization. In order to elucidate how miR-223 regulates the function of macrophages, we generated bone marrow-derived macrophage (BMDM) and tested their response to different stimuli. Our results showed that miR-223 deficiency did not affect macrophage formation in mice. However, miR-223 deficiency enhanced the classical activation (M1) but delayed alternative activation (M2) in macrophages. When stimulated by LPS, miR-223-/- BMDMs exhibited stronger response compared to wild type control cells at various time points, accompanied by increased phosphorylation of p65, suggesting enhanced NF-κB signaling. On the contrary, alternative stimulation by IL-4 led to delayed response in BMDM with miR-223 deficiency judged by surface marker detection using FACS analysis. Consequently, co-culture of miR223-deficient macrophages with wild-type adipocytes led to increased adipocyte inflammatory response and decreased insulin signaling. In addition we investigated the modulation of adipose tissue inflammation by miR-223 in vivo. Upon high-fat diet (HFD) feeding, miR223-deficient mice exhibited a greater increase in the severity of systemic insulin resistance compared to wild-type littermates. Additionally, miR223-deficient mice exhibited a marked increase in HFD-induced adipose tissue inflammatory response. Using a combination of computational prediction and luciferase reporter assays, we identified several genes that are crucial for macrophage activation as miR-223 targets, including Nfat5 and Pknox1. Our findings suggest that miR223 protect against diet-induced adipose tissue inflammatory response by modulating macrophage polarization. thus provides a new layer of regulatory circuit in the network governing adipose tissue inflammation.
- © 2011 by American Heart Association, Inc.