Skap2 Regulates Atherosclerosis through Macrophage Polarization and Efferocytosis

RationaleAtherosclerosis causes more deaths than any other pathophysiologic process. It has a well-established inflammatory, macrophage-mediated component, but important and potentially protective intracellular macrophage processes in atherosclerosis remain enigmatic. Src Kinase-Associated Phosphoprotein 2 (Skap2) is a macrophage-predominant adaptor protein critical for cytoskeletal reorganization, and thereby, for macrophage migration and chemotaxis. The role of macrophage Skap2 in atherosclerosis is unknown and deserves exploration. ObjectiveTo establish the critical role of Skap2 in macrophage-mediated atherosclerotic plaque homeostasis. ResultsIn human arterial gene expression analysis, Skap2 expression is enriched in macrophage-containing areas of human atheroma, and the transcript level varies with plaque characteristics. We have discovered that deletion of Skap2 accelerates atherosclerosis by threefold in ApoE-/- mice on standard diet. Skap2 expression is switched on only as monocytes differentiate into macrophages, so Skap2-/- monocytes have no defect in infiltrating the atheroma. On the other hand, once they fully differentiate, Skap2-deficient macrophages cannot polarize efficiently into alternatively-activated, regulatory cells, and instead they preferentially polarize toward the classical pro-inflammatory phenotype both ex vivo and within the developing atheroma. This defect extends to polarized effector functions, as ex vivo analysis of macrophage phagocytosis of dying foam cells indicates that Skap2 is required for the regulatory process of efferocytosis. ConclusionsTaken together, our findings support a model in which Skap2 drives a regulatory, efferocytic mode of behavior to quell atherosclerosis. CONDENSED ABSTRACT / SUMMARYSkap2--a macrophage protein found in the human atheroma--is atheroprotective. Skap2-null mice, whose foam cells do not migrate well due to a defect in integrin-induced cytoskeletal rearrangement, have accelerated atherosclerosis. Skap2 is not expressed in monocytes but becomes important once they reach the atheroma and become macrophage foam cells, at which point it drives toward a regulatory, anti-inflammatory polarization state required for efficient efferocytosis of dying foam cells. Thus, Skap2 drives a protective, regulatory mode of behavior, supporting the fact that macrophages are not solely deleterious in atherosclerosis, and further pointing to efferocytosis as a target for therapy. There are no relationships to disclose.