title: CYP450-derived oxylipins mediate inflammatory resolution.
abstract: Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid- and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1(+), Ly6c(hi), CCR2(hi), CCL2(hi), and CX3CR1(lo) In addition, expression of F4/80 and the recruitment of T cells, B cells, and dendritic cells were suppressed. sEH (Ephx2)(-/-) mice, which have elevated epoxy-oxylipins, demonstrated opposing effects to epoxI-treated mice: reduced Ly6c(hi) monocytes and elevated F4/80(hi) macrophages and B, T, and dendritic cells. Ly6c(hi) and Ly6c(lo) monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London WC1E 6JJ, United Kingdom; d.gilroy@ucl.ac.uk dbishopbailey@rvc.ac.uk.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Gilroy
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Matthew L
authors.identifier: 0000-0002-7042-500X
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London WC1E 6JJ, United Kingdom;
authors.forename: Roel P H
authors.initials: RP
authors.lastname: De Maeyer
authors.affiliation: William Harvey Research Institute, Barts and The London, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Jonas
authors.initials: J
authors.lastname: Bystrom
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London WC1E 6JJ, United Kingdom;
authors.forename: Justine
authors.initials: J
authors.lastname: Newson
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Division of Medicine, University College London, London WC1E 6JJ, United Kingdom;
authors.forename: Melanie
authors.initials: M
authors.lastname: Stables
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709;
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, United Kingdom d.gilroy@ucl.ac.uk dbishopbailey@rvc.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D054883:Oxylipins / Q000378:metabolism*; D010538:Peritonitis / Q000378:metabolism*; D010587:Phagocytosis
chemical_list: D054883:Oxylipins; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases
keywords: epoxygenase; monocyte; oxylipins; phagocytosis; resolution