Heme oxygenase-1 and carbon monoxide regulate intestinal homeostasis and mucosal immune responses to the enteric microbiota

Abstract

Heme oxygenase-1 (HO-1) and its enzymatic by-product carbon monoxide (CO) have emerged as important regulators of acute and chronic inflammation. Mechanisms underlying their anti-inflammatory effects are only partially understood. In this addendum, we summarize current understanding of the role of the HO-1/ CO pathway in regulation of intestinal inflammation with a focus on innate immune function. In particular, we highlight our recent findings that HO-1 and CO ameliorate intestinal inflammation through promotion of bacterial clearance. Our work and that of many others support further investigation of this global homeostatic pathway in the human inflammatory bowel diseases (IBDs). IntroductionThe maintenance of immune homeostasis in the intestine requires a complex interplay between host and environmental factors that regulate immune responses directed against the enteric microbiota. Loss of tolerance to the enteric microbiota is a unifying pathogenic hypothesis in the initiation and perpetuation of chronic intestinal inflammation.1 Our studies were conceived to understand mechanistically the impact of clinically relevant environmental factors on host-microbiota interactions in IBD. An important epidemiologic observation in the human IBDs is that cigarette smoking is protective against development of ulcerative colitis (UC).

Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology

“…Similarly to above mentioned observations, CORM-3 significantly reduced intestinal inflammation and oxidative stress in postoperative ileus due to activation of p38 MAPK and downregulation of ERK1/2 [48]. Taken together, it can be assumed that CO has immunomodulatory properties and affects the activity of various cell types including T cells, B cells, epithelial cells, neutrophils, mast cells, dendritic cells and macrophages stimulated in the course of gastrointestinal digestive disorders [49]. Takagi et al investigated the effects of CO-releasing CORM-A1 on Th17 differentiation using T-cell transfer-induced colitis in mice [50].…”

“…They revealed that CORM-A1 ameliorated intestinal inflammation through reduction of retinoid related orphan receptor (ROR)γ-receptor expression, inhibition of Th17 differentiation and by the decrease of IL-17A level [50]. HMOX-1/CO pathway can also regulate intestinal inflammation in acute and chronic experimental models by cross-talk of this pathway proteins with enteric microbiota in mucosal immune compartment [49]. Undoubtedly, CO could be considered as potential therapeutic agent in various GI disorders due to the wide range of molecular inflammatory and anti-inflammatory targets affected by this small gaseous molecule.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Moreover, cytoprotective molecules that are under the transcriptional control of NRF2 in eukaryotes can also be produced by commensal bacteria. For instance, the HO-1 homologs in the microbiota may greatly contribute to GI homeostasis, and this can be therapeutically exploited for local delivery of carbon monoxide to the intestine (Onyiah et al, 2014).…”

Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis

“…For example, HO-1 deficiency not only results in inadequate pathogen clearance (14) but also promotes the development of necrotizing enterocolitis-like intestinal injury in mice (15). HO-1 and HO-1-induced carbon monoxide can ameliorate intestinal inflammation through promotion of bacterial clearance (16). The HO-1/carbon monoxide pathway also suppresses Toll-like receptor 4 (TLR4) signaling, leading to downregulation of proinflammatory signaling induced by stimulation with LPS (17).…”