Resolvin D2 limits senescent cell accumulation in atherosclerotic plaques.

Abstract

Atherosclerosis is a non-resolving inflammatory disease, and mechanisms to promote inflammation resolution, reduce vascular injury and promote repair in atherosclerosis are unmet needs. Specialized pro-resolving mediators (SPMs) like Resolvins, in part, mediate inflammation resolution and limit atherosclerosis progression. Uncovering processes associated with their protective actions are of interest. Senescent cells are maladaptive in atherosclerosis, and their accumulation promotes necrotic core formation in plaques. The SPM Resolvin D2 (RvD2) reduces plaque necrosis in part through its G-protein coupled receptor (GPCR), called GPR18. Here, we show how RvD2 can limit senescent cell accumulation in vivo and in vitro. Loss of myeloid GPR18 in Ldlr^-/- mice led to increased accumulation of senescent cells, and RvD2 treatment in Ldlr^-/- mice led to decreased accumulation of senescent cells in plaques. We found that senescent macrophages are not readily efferocytozed due to elevated "don't eat me" signals called CD24 and CD47. Knockdown or blockade of these signals improved senescent macrophage clearance, but not as efficient as efferocytosis of apoptotic cells in vitro. RvD2 treatment to senescent macrophages in vitro increased Cleaved Caspase-3 (an apoptosis marker) but did not impact the levels of CD24 or CD47. RvD2 enhanced the clearance of senescent macrophages but knockdown or blockade of CD24 and CD47 were also required for efficient clearance. Our work provides a cellular mechanism in which RvD2 treatment may limit plaque necrosis through decreasing senescent macrophages in plaques.