Abstract 456: Myeloid RvD2-GPR18 Signaling Axis Limits Plaque Necrosis

Abstract

Introduction: Dysregulated inflammation-resolution programs are associated with atherosclerosis progression. Inflammation-resolution is in part mediated by Resolvins, including Resolvin D2 (RvD2). Previous studies suggested that RvD2 was decreased as atherosclerosis progressed to the advanced stage and that treatment of RvD2 to mice limited plaque progression. Endogenous RvD2 signaling and cellular targets of RvD2 are not known. Methods and Results: Here we developed humanized GPR18 floxed (fl/fl) and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. We employed two different models to evaluate the role of GPR18 in atherosclerosis. We first used the PCSK9-gain of function approach and found increased necrosis in the plaques of the mKO mice compared with fl/fl mice. Next, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr -/- recipients. For these experiments, we treated each genotype with either Veh or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). First, we corroborate our previous results and found the myeloid loss of GPR18 resulted in significantly larger necrotic cores compared with fl/fl transplanted mice. RvD2 treatment decreased plaques necrosis in fl/fl, but not in the mKO transplanted mice. Conclusions: These results are the first to suggest a causative role for endogenous RvD2 signaling on myeloid cells in limiting plaque necrosis. Moreover, these results provide a mechanistic basis for RvD2 as a therapy limiting plaque necrosis.