Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance
- Authors
- Onyiah, J.C., Sheikh, S.Z., Maharshak, N., Steinbach, E.C., Russo, S.M., Kobayashi, T., Mackey, L.C., Hansen, J.J., Moeser, A.J., Rawls, J.F., Borst, L.B., Otterbein, L.E., and Plevy, S.E.
- ID
- ZDB-PUB-121227-18
- Date
- 2013
- Source
- Gastroenterology 144(4): 789-798 (Journal)
- Registered Authors
- Mackey, Lantz, Rawls, John F.
- Keywords
- mouse model, IBD, ulcerative colitis, anti-inflammatory agent
- MeSH Terms
-
- Animals
- Bacterial Translocation/drug effects
- Bacterial Translocation/physiology*
- Blotting, Western
- Carbon Monoxide/pharmacology*
- Colitis/drug therapy
- Colitis/microbiology
- Colitis/prevention & control*
- Disease Models, Animal
- Escherichia coli/pathogenicity
- Gentamicins/pharmacology
- Heme Oxygenase-1/biosynthesis
- Heme Oxygenase-1/metabolism*
- Macrophages/cytology
- Macrophages/physiology
- Metagenome
- Mice
- Mice, Inbred C57BL
- Random Allocation
- Real-Time Polymerase Chain Reaction
- Salmonella typhimurium/physiology*
- PubMed
- 23266559 Full text @ Gastroenterology
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, andIl10-/-mice and germ free zebrafish embryoswere colonized with pathogen-free (SPF). Germ-free or SPF-raised wild-type andIl10-/-mice were given intraperitoneal injections of cobalt protoporphyrin (CoPP), which upregulates HO-1, the CO releasing molecule ALF186, or saline (control). Colitis was induced in wild-type mice housed in SPF conditions by infection with S. typhimurium.
Results
In colons of germ-free, wild-type mice, SPF microbiota induced production of HO-1 via activation of Nrf2–, 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-freeIl10-/-mice. Administration of CoPP toIl10-/-mice before transition from germ-free to SPF conditions reduced their development of colitis. InIl10-/-mice, CO and CoPP reduced levels of enteric bacterial genomic DNA in mesenteric lymph nodes (MLN). In mice withS. typhimurium -induced enterocolitis, CoPP reduced the numbers of liveS. typhimurium recovered from the lamina propria, MLN, 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.