Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn’s disease
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.
Authors
- Melissa Ellermann (ORCID: https://orcid.org/0000-0002-8942-6889)
- Lee A. Denson (ORCID: https://orcid.org/0000-0001-8045-7198)
- Lacey R. Lopez (ORCID: https://orcid.org/0000-0002-5667-8107)
- Marlus da Silva Pedrosa (ORCID: https://orcid.org/0000-0002-4052-7208)
- Taylor Tibbs (ORCID: https://orcid.org/0000-0003-3663-9570)
- William C. Zamboni (ORCID: https://orcid.org/0000-0002-8319-4482)
- Yen‐Rei Yu (ORCID: https://orcid.org/0000-0002-1984-7186)
- Janelle C. Arthur (ORCID: https://orcid.org/0000-0002-4796-0207)
- Aaron Rothemich
- Joanna Jeyachandran
- Ju-Hyun Ahn
- Ian Cumming
- Corey J Haswell
- Emily Vignieri
- Alexander D Irmscher
Institutions
- University of North Carolina at Chapel Hill (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of North Carolina Health Care (US)
- University of South Carolina (US)
- Duke University (US)
- Duke University Hospital (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1016/j.chom.2024.11.012
- Citations
- 12
- Primary Topic
- Inflammatory Bowel Disease
- Type
- article
- Field-Weighted Citation Impact
- 6.60
Funders
- Foundation for the National Institutes of Health
- Cincinnati Children's Hospital Medical Center
- Cleveland Clinic
- Kenneth Rainin Foundation
- Crohn's and Colitis Foundation
- National Institutes of Health
- National Cancer Institute
- National Institute of Allergy and Infectious 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