Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance

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 Il10−/− mice and germ free zebrafish embryos were colonized with pathogen-free (SPF). Germ-free or SPF-raised wild-type and Il10−/− 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-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 (MLN). In mice with S. typhimurium-induced enterocolitis, CoPP reduced the numbers of live S. 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.

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

“…Additionally, we observed a significant increase in HO-1 expression in both murine macrophage RAW264.7 and hepatoma Hepa1-6 cells (unpublished data). This is consistent with previously published studies demonstrating an upregulation of HO-1 mRNA and/or protein expression in response to bacterial (29,(40)(41)(42)(43)(44)(45) or parasitic (26,27,46) infections and might be a general response of infected host cells.…”

“…HO-1 is able to promote Plasmodium liver infection (26), whereas it plays a favorable role in the host during cerebral malaria (27). HO-1 also enhances bacterial clearance during CLP-mediated polymicrobial sepsis (28) and Salmonella typhimurium-induced enterocolitis (29).…”

Molecular Mechanisms Used by Salmonella to Evade the Immune System

“…This is likely due to the increase in oxidative stress and inflammation (reviewed in Blancou et al, 2011). Onyiah et al (2013). using a colitis mouse model, showed that the enteric microbiota induces expression of HO-1 in mice and zebrafish.…”

Association of Heme Oxygenase 1 with the Restoration of Liver Function after Damage in Murine Malaria by Plasmodium yoelii

“…HO-1 plays a major role as a cytoprotective and antiinflammatory protein in many diseases (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Induction of HO-1 is necessary for the resolution phase of wound healing, including amelioration of inflammation, proliferation, and protection against apoptosis (35).…”