TY - JOUR
T1 - Carbon monoxide and heme oxygenase-1 prevent intestinal inflammation in mice by promoting bacterial clearance
AU - Onyiah, Joseph C.
AU - Sheikh, Shehzad Z.
AU - Maharshak, Nitsan
AU - Steinbach, Erin C.
AU - Russo, Steven M.
AU - Kobayashi, Taku
AU - Mackey, Lantz C.
AU - Hansen, Jonathan J.
AU - Moeser, Adam J.
AU - Rawls, John F.
AU - Borst, Luke B.
AU - Otterbein, Leo E.
AU - Plevy, Scott E.
N1 - Funding Information:
Funding Supported by National Institutes of Health grants R01 DK54452 (S.E.P.), R01 DK081426 (J.F.R.), and K08 DK084313 (A.J.M.); Gastroenterology Research Training grant T32 DK007737 (S.Z.S. and J.C.O.); National Research Service Award F32 DK083186 (S.Z.S.); University of North Carolina Center for Gastrointestinal Biology and Disease P30 DK034987 grant (Immunotechnologies, Gnotobiotic, and Histology Cores), and a Crohn's and Colitis Foundation of America Research Fellowship award (N.M. and T.K.).
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Anti-Inflammatory Agent
KW - IBD
KW - Mouse Model
KW - Ulcerative Colitis
UR - http://www.scopus.com/inward/record.url?scp=84875278108&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2012.12.025
DO - 10.1053/j.gastro.2012.12.025
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AN - SCOPUS:84875278108
SN - 0016-5085
VL - 144
SP - 789
EP - 798
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -