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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Onyiah, JC; Sheikh, SZ; Maharshak, N; Steinbach, EC; Russo, SM; Kobayashi, T; Mackey, LC; Hansen, JJ; Moeser, AJ; Rawls, JF; Borst, LB; Otterbein, LE; Plevy, SE

Published Date

  • April 2013

Published In

Volume / Issue

  • 144 / 4

Start / End Page

  • 789 - 798

PubMed ID

  • 23266559

Pubmed Central ID

  • PMC3608700

Electronic International Standard Serial Number (EISSN)

  • 1528-0012

Digital Object Identifier (DOI)

  • 10.1053/j.gastro.2012.12.025


  • eng

Conference Location

  • United States