title: Identification of resolvin D2 receptor mediating resolution of infections and organ protection.
abstract: 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 (3)H-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.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115.
authors.forename: Nan
authors.initials: N
authors.lastname: Chiang
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115 cnserhan@zeus.bwh.harvard.edu.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D004926:Escherichia coli; D055785:Gene Knockdown Techniques; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D014316:Tritium; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D017931:DNA Primers; C571204:GPR18 protein, mouse; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C545423:resolvin D2; D014316:Tritium; D004281:Docosahexaenoic Acids; D000242:Cyclic AMP