Gabrielle Fredman

Dysregulated inflammation‐resolution programs are associated with atherosclerosis progression. Resolvins, in part, mediate inflammation‐resolution programs. Indeed, Resolvin D2 (RvD2) activates GPR18, a G‐protein‐coupled receptor, and limits plaque progression, though the cellular targets of RvD2 remain unknown. Here, we developed a 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. To understand the functions of RvD2‐GPR18 in atherosclerosis, 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 Vehicle/PBS or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis, increased cleaved caspase‐3 + cells and decreased percentage of Arginase‐1 + ‐Mac2 + cells without a change in overall Mac2 + plaque macrophages, compared with fl/fl➔ Ldlr −/− transplanted mice. RvD2 treatment decreased plaque necrosis, the percent of cleaved caspase‐3 + cells and increased the percent of Arginase‐1 + ‐Mac2 + cells in fl/fl➔ Ldlr −/− mice, but not in the mKO➔ Ldlr −/− transplanted mice. These results suggest that GPR18 plays a causal role in limiting atherosclerosis progression and that RvD2's ability to limit plaque necrosis is in part dependent on myeloid GRP18.