Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn’s disease
Year: 2024
Type: article
Abstract: Inflammatory bowel disease (IBD)-associated fibrosis causes significant morbidity. Mechanisms are poorly understood but implicate the microbiota, especially adherent-invasive Escherichia coli (AIEC). We previously demonstrated that AIEC producing the metallophore yersiniabactin (Ybt) promotes intestinal fibrosis in an IBD mouse model. Since macrophages interpret microbial signals and influence inflammation/tissue remodeling, we hypothesized that Ybt metal sequestration disrupts this process. Here, we show that macrophages are abundant in human IBD-fibrosis tissue and mouse fibrotic lesions, where they co-localize with AIEC. Ybt induces profibrotic gene expression in macrophages via stabilization and nuclear translocation of hypoxia-inducible factor 1-alpha (HIF-1α), a metal-dependent immune regulator. Importantly, Ybt-producing AIEC deplete macrophage intracellular zinc and stabilize HIF-1α through inhibition of zinc-dependent HIF-1α hydroxylation. HIF-1α+ macrophages localize to sites of disease activity in human IBD-fibrosis strictures and mouse fibrotic lesions, highlighting their physiological relevance. Our findings reveal microbiota-mediated metal sequestration as a profibrotic trigger targeting macrophages in the inflamed intestine.
Source: Cell Host & Microbe
Language: English
Topic: Inflammatory Bowel Disease
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Funders: Foundation for the National Institutes of Health, University of North Carolina, Cincinnati Children's Hospital Medical Center, Cleveland Clinic, Kenneth Rainin Foundation, Crohn's and Colitis Foundation, UVA Cancer Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Duke Cancer Institute, Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill
Awards: G1174881085, G166906552, G1948135505, G2627953802, G2710223138, G2861655289, G3371829752, G402423035, G407118926, G4126106502, G4599006993, G5445586208, Role of Resident Monocytes in the Pathogenesis of Pulmonary Arterial Hypertension, Intestinal inflammation and genotoxicity of the colonic-adherent microbiota, G704522546, G705871567, G7060891583, G7149059628, G726513172, G7366156696, Effects of host endocannabinoid signaling on Enterobacteriaceae infection, G8494136112, G880221860, G9000002568, G9000033364, G9000062106, G9000087880, G9000114373, G9000295917, Cancer Center Support Grant, G958207224
OpenAlex ID: W4405532191