Identification of resolvin D2 receptor mediating resolution of infections and organ protection.
Identification of resolvin D2 receptor mediating resolution of infections and organ protection.
复制标题
DOI：
10.1084/jem.20150225
复制
发表时间：
2015-07-27
期刊：
影响因子：
--
通讯作者：
Serhan CN
中科院分区：
文献类型：
--
作者：
Chiang N;Dalli J;Colas RA;Serhan CN
蒋等人将GPR18鉴定为消退素D2的一种新型受体，并表明在人类和小鼠吞噬细胞中激活该受体可在细菌感染期间刺激吞噬清除作用，并促进器官保护。
协调急性炎症消退的内源性机制在宿主防御和恢复内稳态中至关重要。消退素（Rv）D2是在炎症主动消退过程中生物合成的一种强效免疫消退剂，它能立体选择性地刺激急性炎症的消退。在此，我们利用一种无偏向性的基于G蛋白偶联受体 - β - 抑制蛋白的筛选和功能传感系统，鉴定出了RvD2的一种受体，即GPR18，它在人类白细胞上表达，包括多形核中性粒细胞（PMN）、单核细胞和巨噬细胞（MΦ）。在人类巨噬细胞中，RvD2刺激的细胞内环磷腺苷（cAMP）依赖于GPR18。RvD2刺激的大肠杆菌吞噬作用以及凋亡PMN的胞葬作用（efferocytosis）在GPR18过表达时增强，而在通过shRNA敲低时显著减弱。利用合成的³H标记的RvD2证实了RvD2与重组GPR18的特异性结合。斯卡查德分析得出的Kd约为10 nM，与RvD2的生物活性浓度范围相符。在大肠杆菌和金黄色葡萄球菌感染中，RvD2限制了PMN的浸润，增强了吞噬细胞对细菌的清除，并加速了炎症消退。这些作用在GPR18缺陷型小鼠中消失。在PMN介导的二次器官损伤过程中，RvD2的保护作用在GPR18缺陷型小鼠中也显著减弱。总之，这些结果为一种新型的RvD2 - GPR18消退轴提供了证据，该轴刺激人类和小鼠吞噬细胞的功能以控制细菌感染并促进器官保护。
Chiang et al. identify GPR18 as a novel receptor for resolvin D2, and show that activation of this receptor in human and mouse phagocytes stimulates phagocytic clearance during bacterial infections and promotes organ protection Endogenous mechanisms that orchestrate resolution of acute inflammation are essential in host defense and the return to homeostasis. Resolvin (Rv)D2 is a potent immunoresolvent biosynthesized during active resolution that stereoselectively stimulates resolution of acute inflammation. Here, using an unbiased G protein–coupled receptor-β-arrestin–based screening and functional sensing systems, we identified a receptor for RvD2, namely GPR18, that is expressed on human leukocytes, including polymorphonuclear neutrophils (PMN), monocytes, and macrophages (MΦ). In human MΦ, RvD2-stimulated intracellular cyclic AMP was dependent on GPR18. RvD2-stimulated phagocytosis of Escherichia coli and apoptotic PMN (efferocytosis) were enhanced with GPR18 overexpression and significantly reduced by shRNA knockdown. Specific binding of RvD2 to recombinant GPR18 was confirmed using a synthetic 3H-labeled-RvD2. Scatchard analysis gave a Kd of ∼10 nM consistent with RvD2 bioactive concentration range. In both E. coli and Staphylococcus aureus infections, RvD2 limited PMN infiltration, enhanced phagocyte clearance of bacteria, and accelerated resolution. These actions were lost in GPR18-deficient mice. During PMN-mediated second organ injury, RvD2’s protective actions were also significantly diminished in GPR18-deficient mice. Together, these results provide evidence for a novel RvD2–GPR18 resolution axis that stimulates human and mouse phagocyte functions to control bacterial infections and promote organ protection.