Necroptosis Impairs Inflammation-Resolution Programs in Atherosclerosis

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Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the industrialized world. Studies over the last decade suggest that failed resolution of a chronic inflammatory response is an important driving force in the progression of atherosclerosis. Accordingly, two critical unanswered questions are: (a) what are the endogenous mechanisms underlying dysregulated resolution programs in atherosclerosis and (b) what mechanism-based treatment strategies can be conceived to initiate resolution when it fails? The resolution of inflammation is regulated, in part, by specialized pro-resolving mediators (SPM) that comprise omega-6 derived lipoxins and omega-3 derived resolvins, protectins and maresins. The overall objective of this proposal is to understand the mechanisms of dysregulated resolution in atherosclerosis and to harness SPM signaling pathways towards a novel treatment strategy. Mechanisms and processes that drive dysregulated resolution programs in atherosclerosis are of interest. Necroptosis, a specific form of programmed cell death, has recently emerged as a driver of atherosclerosis progression. Our new work suggests that necroptosis itself impairs endogenous resolution programs and that key SPMs can limit necroptotic signaling. We proposed a series of studies to identify the mechanisms associated with necroptosis and impaired resolution (Aim I), the link between necroptosis and SPM formation in plaques (Aim II) and mechanisms underlying how SPMs evoke their anti-necroptotic actions on macrophages (Aim III). The link between dysregulated resolution programs and necroptosis is a completely new and unexplored area of research that may reveal new treatment strategies for atherosclerosis that are complementary to those that currently exist.