Abstract 19821: Integrin αDβ2 (CD11d/CD18) Promotes Atherogenesis by Supporting Macrophage Retention in Atherosclerotic Lesions
Understanding the mechanism of macrophage retention in atherosclerotic lesions is a key question in the control of atherogenesis. Integrin αDβ2 (CD11d/CD18) is a multiligand leukocyte adhesive receptor with unidentified functions. Previously we found that CD11d overexpression on cell surface inhibits cell migration due to excessive adhesive force. Currently, we found that CD11d expression is dramatically upregulated on macrophages in atherosclerotic lesions and on pro-inflammatory M1 macrophages in vitro. Hence, we hypothesized that high expression of CD11d promotes atherogenesis and serves for the retention of pro-inflammatory macrophages in atherosclerotic lesions.
To test our hypothesis we generated CD11d-/-/ApoE-/- mice and evaluated atherogenesis after 16 weeks on a Western diet. CD11d-deficiency markedly reduced lipid deposition in the entire aorta (2.12-fold) and aorta sinuses (1.53-fold). Macrophage number in aorta sinuses of CD11d-/- mice was also significantly reduced without affecting their apoptosis and proliferation, which indicates a potential role of CD11d in migration-related macrophage accumulation. The effect of CD11d on macrophage migration/retention was tested using adoptive transfer of wild type (WT) and CD11d-/- monocytes labeled with two non-overlapping near-infrared fluorescent dyes. Equal numbers of WT and CD11d-/- monocytes were injected into the tail vein of ApoE-/- mice and their accumulation in atherosclerotic lesions was assessed at 72 hrs. The result showed a similar monocyte emigration from the circulation, but significantly reduced number of labeled CD11d-/- macrophages in the aortas (2.4-fold). The contribution of CD11d to macrophage retention was further verified in the model of resolution of peritoneal inflammation. Fluorescently-labeled WT and CD11d-/- M1 macrophages were injected intraperitoneally to WT mice with pre-conditioned thioglycollate-induced peritoneal inflammation. The efflux of CD11d-deficient macrophages was 1.8-fold faster from the peritoneal cavity which confirms improved migratory properties of CD11d-/- macrophages. In summary, macrophage CD11d is involved in atherogenesis by the contribution to the retention of M1 macrophages in the atherosclerotic lesions.
Author Disclosures: M. Aziz: None. K. Brown: None. K. Cui: None. J. Han: None. J.D. Smith: None. V.P. Yakubenko: None.
- © 2016 by American Heart Association, Inc.