Abstract 17866: Macrophage Integrin aDβ2 (CD11d/CD18) Promotes Atherogenesis, Diet-Induced Insulin Resistance and Glucose Intolerance in Mice
Low-grade chronic inflammation is a critical factor in atherogenesis and obesity-mediated diabetes. The purpose of this study is to test the role of the leukocyte migratory receptor, integrin αDβ2 (CD11d/CD18) in the inflammatory response. Noting that this integrin, which recognizes many different extracellular matrix proteins, is poorly expressed on peripheral blood leukocytes but is dramatically upregulated on macrophage foam cells during atherogenesis and on adipose tissue macrophages during obesity, we hypothesized that αDβ2 may play an important role in the development of chronic inflammation in peripheral tissues.
To test our hypothesis we generated αD-/-/ApoE-/- mice and evaluated the development of atherosclerosis in male mice after 16 weeks on a western diet. We found that αD-deficiency markedly reduced lipid deposition in the entire aorta (2.12-fold, P<0.001) and aorta sinuses (1.53-fold, P=0.014).There were ~3.5-fold less foam cells in the macrophages isolated from αD-/-/ApoE-/- mice compared with ApoE-/- control (P<0.01). This result was confirmed using in vivo foam cell formation. When WT and αD-/- macrophages were injected to peritoneum of ApoE-/- mice, four days later, isolated αD-/- macrophages showed decreased uptake of oxLDL. To test the role of αD in obesity-mediated diabetes, wild type and αD-/- mice were placed on a high fat diet for 22 weeks and metabolic parameters were evaluated. We found that αD-deficiency markedly reduced insulin resistance and glucose intolerance. Furthermore, the number of macrophages in adipose tissue of αD-/- mice was decreased by ~3 fold. In vitro analysis of polarized macrophages indicated almost a 4-fold enhancement of αD expression on M1 macrophages and a 2-fold decrease on M2 macrophages (compared to initial level).
Therefore, our data demonstrate that integrin αD has pro-inflammatory effects on the development of atherosclerosis and diabetes. We suggest that this outcome is mediated by the upregulation of αDβ2 on classically activated macrophages at the site of inflammation, that can promote retention of M1 macrophages in the inflamed peripheral tissues.
- © 2013 by American Heart Association, Inc.