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bioRxiv · 10.1101/2023.04.03.535493

Resolvin D2-GPR18 Signaling on Myeloid Cells Limits Plaque Necrosis

Fredman, G.·Lipscomb, M.·Walis, S.·Marinello, M.·Mena, H. A.·Spite, M.
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Abstract

Introduction/ObjectiveDysregulated 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 ResultsHere 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. ConclusionsThese 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.

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Fredman, G., Lipscomb, M., Walis, S., Marinello, M., Mena, H. A., Spite, M.. 2023-04-05. Resolvin D2-GPR18 Signaling on Myeloid Cells Limits Plaque Necrosis. https://doi.org/10.1101/2023.04.03.535493

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