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Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.

ABSTRACT: Resolution of acute inflammation is an active event accompanied by biosynthesis of specialized proresolving mediators (SPM). We employed a systems approach to determine the impact of CO in resolution active programs during self-limited inflammation in mice. Compared with ambient air, inhaled CO gas (250 ppm) significantly limited PMN infiltration (?44%, 6 h) into peritoneum and shortened resolution interval from 4 to 2 h. We profiled exudate lipid mediators (LM) via metabololipidomics, CO reduced leukotriene B4 (21 ± 11 versus 59 ± 24 pg/mouse, 6 h), and elevated SPM including resolvin (Rv) D1 (27 ± 4 versus 16 ± 5 pg/mouse) and maresin 1 (26 ± 9 versus 15 ± 3 pg/mouse). With human macrophages, SPM (10 pM-10 nM) elevated heme oxygenase (HO)-1 (?50%, 8 h). CO also enhanced HO-1 expression and accumulation of RvD1 and RvD5, an action reversed by blockage of a key SPM biosynthesis enzyme 15-lipoxygenase type 1. Compared with normoxia, CO increased ?30% phagocytosis of opsonized zymosan with human macrophage, which was further enhanced by SPM (?100%). This CO increased phagocytosis was blocked by 15-lipoxygenase inhibition, and SPM stimulated phagocytosis was diminished by HO-1 inhibition. In murine peritonitis, both pre- and posttreatment with CO inhalation significantly increased macrophages carrying ingested apoptotic PMN in exudates and enhanced PMN apoptosis. Taken together, these results indicate that CO accelerates resolution of acute inflammation, shortens resolution intervals, enhances macrophage efferocytosis, and temporally regulates local levels of lipid mediator/SPM. Moreover, they provide proresolving mechanisms for HO-1/CO, which is part of the SPM-initiated resolution circuit.

SUBMITTER: Chiang N

PROVIDER: S-EPMC3679316 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.

Chiang Nan N Shinohara Masakazu M Dalli Jesmond J Mirakaj Valbona V Kibi Megumi M Choi Augustine M K AM Serhan Charles N CN

Journal of immunology (Baltimore, Md. : 1950) 20130506 12

Resolution of acute inflammation is an active event accompanied by biosynthesis of specialized proresolving mediators (SPM). We employed a systems approach to determine the impact of CO in resolution active programs during self-limited inflammation in mice. Compared with ambient air, inhaled CO gas (250 ppm) significantly limited PMN infiltration (∼44%, 6 h) into peritoneum and shortened resolution interval from 4 to 2 h. We profiled exudate lipid mediators (LM) via metabololipidomics, CO reduce ...[more]

PMID: 23650615

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Project description:BACKGROUND & AIMS:Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish. METHODS:Germ-free, wild-type, and interleukin (Il)10(-/-) mice and germ-free zebrafish embryos were colonized with specific pathogen-free (SPF) microbiota. Germ-free or SPF-raised wild-type and Il10(-/-) mice were given intraperitoneal injections of cobalt(III) protoporphyrin IX chloride (CoPP), which up-regulates HO-1, the CO-releasing molecule Alfama-186, or saline (control). Colitis was induced in wild-type mice housed in SPF conditions by infection with Salmonella typhimurium. RESULTS:In colons of germ-free, wild-type mice, SPF microbiota induced production of HO-1 via activation of nuclear factor erythroid 2-related factor 2-, IL-10-, and Toll-like receptor-dependent pathways; similar observations were made in zebrafish. SPF microbiota did not induce HO-1 in colons of germ-free Il10(-/-) mice. Administration of CoPP to Il10(-/-) mice before transition from germ-free to SPF conditions reduced their development of colitis. In Il10(-/-) mice, CO and CoPP reduced levels of enteric bacterial genomic DNA in mesenteric lymph nodes. In mice with S typhimurium-induced enterocolitis, CoPP reduced the numbers of live S typhimurium recovered from the lamina propria, mesenteric lymph nodes, spleen, and liver. Knockdown of HO-1 in mouse macrophages impaired their bactericidal activity against E coli, E faecalis, and S typhimurium, whereas exposure to CO or overexpression of HO-1 increased their bactericidal activity. HO-1 induction and CO increased acidification of phagolysosomes. CONCLUSIONS:Colonic HO-1 prevents colonic inflammation in mice. HO-1 is induced by the enteric microbiota and its homeostatic function is mediated, in part, by promoting bactericidal activities of macrophages.

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Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.

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Inhaled carbon monoxide accelerates resolution of inflammation via unique proresolving mediator-heme oxygenase-1 circuits.

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