Wip1-dependent modulation of macrophage migration and phagocytosis

Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis. Controlling macrophage conversion into foam cells remains a major challenge for treatment of atherosclerotic diseases. Here, we show that Wip1, a member of the PP2C family of Ser/Thr protein phosphatases, modulates macrophage migration and phagocytosis associated with atherosclerotic plaque formation. Wip1 deficiency increases migratory and phagocytic activities of the macrophage under stress conditions. Enhanced migration of Wip1(-/-) macrophages is mediated by Racl-GTPase and PI3IC/AKT signalling pathways. Elevated phagocytic ability of Wip1(-/-) macrophages is linked to CD36 plasma membrane recruitment that is regulated by AMPK activity. Our study identifies Wip1 as an intrinsic negative regulator of macrophage chemotaxis. We propose that Wip1-dependent control of macrophage function may provide avenues for preventing or eliminating plaque formation in atherosclerosis.Major National Scientific Research Projects [2015CB943100]; National Natural Science Foundation of China [31330074, 31572378, 31272404]; National High Technology Research and Development Program of China [2012AA020603]; Agricultural Science and Technology Innovation Program [ASTIP-IAS05]; National Institutes of Health [R01AR070752]SCI(E)ARTICLE665-6731