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

Publication ,  Journal Article
Onyiah, JC; Sheikh, SZ; Maharshak, N; Steinbach, EC; Russo, SM; Kobayashi, T; Mackey, LC; Hansen, JJ; Moeser, AJ; Rawls, JF; Borst, LB ...
Published in: Gastroenterology
April 2013

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.

Duke Scholars

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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

April 2013

Volume

144

Issue

4

Start / End Page

789 / 798

Location

United States

Related Subject Headings

  • Salmonella typhimurium
  • Real-Time Polymerase Chain Reaction
  • Random Allocation
  • Mice, Inbred C57BL
  • Mice
  • Metagenome
  • Macrophages
  • Heme Oxygenase-1
  • Gentamicins
  • Gastroenterology & Hepatology
 

Citation

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Onyiah, J. C., Sheikh, S. Z., Maharshak, N., Steinbach, E. C., Russo, S. M., Kobayashi, T., … Plevy, S. E. (2013). Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance. Gastroenterology, 144(4), 789–798. https://doi.org/10.1053/j.gastro.2012.12.025
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

April 2013

Volume

144

Issue

4

Start / End Page

789 / 798

Location

United States

Related Subject Headings

  • Salmonella typhimurium
  • Real-Time Polymerase Chain Reaction
  • Random Allocation
  • Mice, Inbred C57BL
  • Mice
  • Metagenome
  • Macrophages
  • Heme Oxygenase-1
  • Gentamicins
  • Gastroenterology & Hepatology