Abstract 137: Skap2 Modulates Macrophage Polarization and Regulates Atherosclerosis
Background: Integrins mediate macrophage behaviors that are central to atherogenesis. Macrophage integrins cooperate with other membrane and adaptor proteins (including CD47, Sirpα, and Skap2) to control integrin-induced actin reorganization and migration. We hypothesized that such signals would impact the progression of atherosclerosis.
Results: Using integrin-binding microbeads applied to bone marrow-derived macrophages (BMMs) from mice with specific gene knockouts, we have found that local actin polymerization requires three major proteins - Sirpα, CD47 and Skap2 - that are known to cooperate in signaling complexes recruited by activated integrins. We introduced Skap2 deficiency to apoE-knockout mice to ascertain how Skap2 modulates atherosclerosis. Skap2-/-;apoE-/- C57BL/6 mice develop increased atherosclerotic plaque in their aortic roots, compared to their Skap2+/+;apoE-/- counterparts, as early as 18 weeks of age on a standard diet. There is no detectable difference in weight, lipid profile, development, or other organ pathology. Skap2-deficient mice have a circulating cytokine profile consistent with a macrophage-centric inflammatory process. While Skap2-deficiency does not impact macropinocytosis or scavenger-receptor-mediated acetylated LDL uptake, the macrophage distribution within the plaque differs significantly from standard murine atheromata with an overall macrophage content proportional to the increased size of the plaque. Finally, Skap2 is prominently expressed in M2 (regulatory) macrophages, and Skap2-deficient BMMs demonstrate impaired expression of M2 markers when stimulated by IL4 in vitro.
Conclusion: Overall, we find that a Skap2-dependent pathway directs macrophage migration and actin reorganization. This pathway contributes to regulation of atherogenesis, maintenance of normal lesional macrophage homeostasis, and polarization of regulatory macrophages.
Author Disclosures: D. Hyatt: None. D. Golan: None. K. Swanson: None. F.J. Alenghat: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.