CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis

Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase gamma (CaMKII gamma) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Macrophages in necrotic and symptomatic atherosclerotic plaques in humans as well as advanced atherosclerotic lesions in mice demonstrated activation of CaMKII. Western diet-fed LDL receptor-deficient (Ldlr(-/-)) mice with myeloid-specific deletion of CaMKII had smaller necrotic cores with concomitantly thicker collagen caps. These lesions demonstrated evidence of enhanced efferocytosis, which was associated with increased expression of the macrophage efferocytosis receptor MerTK. Mechanistic studies revealed that CaMKII gamma-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKII gamma had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-alpha (LXR alpha), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKII gamma-deficient macrophages is dependent on LXR alpha. These findings identify a macrophage CaMKII gamma/ATF6/LXR alpha/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.