Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance

Joseph C. Onyiah, Shehzad Z. Sheikh, Nitsan Maharshak, Erin C. Steinbach, Steven M. Russo, Taku Kobayashi, Lantz C. Mackey, Jonathan J. Hansen, Adam J. Moeser, John F. Rawls, Luke B. Borst, Leo E. Otterbein, Scott E. Plevy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)789-798
Number of pages10
JournalGastroenterology
Volume144
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Funding

FundersFunder number
Crohn's and Colitis Foundation of America
National Institutes of HealthR01 DK54452, K08 DK084313, R01 DK081426
University of North Carolina Center for Gastrointestinal Biology and DiseaseP30 DK034987
Gastroenterology Research Training grantT32 DK007737, F32 DK083186

    Keywords

    • Anti-Inflammatory Agent
    • IBD
    • Mouse Model
    • Ulcerative Colitis

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