Introduction/objective: Dysregulated inflammation-resolution programs are associated with atherosclerosis progression. Inflammation-resolution is in part mediated by Resolvins, including Resolvin D2 (RvD2). RvD2, which activates a G-protein coupled receptor (GPCR) called GPR18, limits plaque progression. Cellular targets of RvD2 are not known.
Approach 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). Myeloid loss of GPR18 resulted in significantly more necrosis and cleaved caspase-3 + cells compared with fl/fl transplanted mice. RvD2 treatment decreased plaques necrosis and cleaved caspase-3 + cells 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.