N-3 docosapentaenoic acid-derived resolvin D5 (RvD5(n-3 DPA)) is diurnally regulated in peripheral blood and exerts tissueprotective actions during inflammatory arthritis. Here, using an orphan GPCR screening approach coupled with functional readouts, we investigated the receptor(s) involved in mediating the leukocyte-directed actions of RvD5(n-3 DPA) and identified GPR101 as the top candidate. RvD5(n-3 DPA) bound to GPR101 with high selectivity and stereospecificity, as demonstrated by a calculated K-D of approximately 6.9 nM. In macrophages, GPR101 knockdown limited the ability of RvD5(n-3 DPA) to upregulate cyclic adenosine monophosphate, phagocytosis of bacteria, and efferocytosis. Inhibition of this receptor in mouse and human leukocytes abrogated the pro-resolving actions of RvD5(n-3 DPA), including the regulation of bacterial phagocytosis in neutrophils. Knockdown of the receptor in vivo reversed the protective actions of RvD5(n-3 DPA) in limiting joint and gut inflammation during inflammatory arthritis. Administration of RvD5(n-3 DPA) during E. coli-initiated inflammation regulated neutrophil trafficking to the site of inflammation, increased bacterial phagocytosis by neutrophils and macrophages, and accelerated the resolution of infectious inflammation. These in vivo protective actions of RvD5(n-3 DPA) were limited when Gpr101 was knocked down. Together, our findings demonstrate a fundamental role for GPR101 in mediating the leukocyte-directed actions of RvD5(n-3 DPA)
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