Critical Mediators of Inflammation Resolution and Immune Memory in Atherosclerosis

PROJECT SUMMARY Despite major medical advances, cardiovascular disease remains the major cause of morbidity and mortality worldwide. Even with aggressive risk factor control, nearly 50% of patients suffer recurrent cardiac events and this “residual risk” has been attributed to excessive inflammation. Recent work has demonstrated that atherosclerosis is also characterized by the failure of inflammation resolution. The resolution program is regulated by the production of specialized pro-resolving lipid mediators (SPMs) and the efficient clearance of apoptotic cells (efferocytosis) from tissue. Advanced atherosclerotic plaques have higher numbers of apoptotic cells, larger necrotic cores, and an imbalance of pro-inflammatory:pro-resolving mediators compared with early lesions, all of which are suggestive of failed resolution. Strategies that boost resolution and break the cycle of chronic inflammation promote plaque stability. Therefore, the identification of novel targets that mediate this process is of critical importance. Our preliminary data have identified Ca2+/Calmodulin-Dependent Protein Kinase IV (CaMK4) as a central regulator of both inflammation and resolution. Uniquely, CaMK4 appears to play an important role in the development of innate immune memory in macrophages, which enhances their pro- inflammatory responses to atherogenic stimuli. Therefore, we hypothesize that CaMK4 is a critical mediator of immune memory and that immune training impairs resolution through a CaMK4-dependent mechanism. We will test our hypothesis through the following aims: Specific Aim 1 will test the hypothesis that myeloid-CaMK4 impairs resolution as a mechanism by which it promotes atheroprogression. Specific Aim 2 will explore the mechanism by which CaMK4 promotes oxLDL training of myeloid progenitors and macrophages in order to augment their inflammatory cytokine production. Specific Aim 3 will test the hypothesis that targeting CaMK4 in advanced atherosclerosis can promote regression of plaque.