N-3 docosapentaenoic acid–derived resolvin D5 (RvD5_{n-3 DPA}) is diurnally regulated in peripheral blood and exerts tissue-protective 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}.

中文翻译：

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GPR101介导RvD5 _{n-3 DPA}在关节炎和感染中的促分解作用

N-3二十碳五烯酸衍生的resolvin D5（RvD5 _{n-3 DPA}）在外周血中被昼夜调节，并在炎症性关节炎中发挥组织保护作用。在这里，使用孤立的GPCR筛选方法与功能读数结合，我们研究了介导RvD5 _{n-3 DPA}的白细胞定向作用的受体，并将GPR101确定为最佳候选者。RvD5 _{n-3 DPA}以高选择性和立体特异性与GPR101结合，计算出的K _D约为6.9 nM。在巨噬细胞中，GPR101敲低限制了RvD5 _{n-3 DPA}的能力上调环状单磷酸腺苷，细菌的吞噬作用和胞吐作用。在小鼠和人类白细胞中抑制该受体消除了RvD5 _{n-3 DPA}的促分解作用，包括中性粒细胞中细菌吞噬作用的调节。体内敲低该受体逆转了RvD5 _{n-3 DPA}在限制炎症性关节炎期间关节和肠道炎症中的保护作用。在大肠杆菌中施用RvD5 _{n-3 DPA}–引发炎症调节嗜中性粒细胞向炎症部位的运输，增加嗜中性粒细胞和巨噬细胞的细菌吞噬作用，并加速传染性炎症的消退。当敲除Gpr101时，RvD5 _{n-3 DPA的}这些体内保护作用受到限制。在一起，我们的发现表明GPR101在介导RvD5 _{n-3 DPA}的白细胞定向作用中起着基本作用。