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Cell Host Microbe, Jan 08 2025, 33 (1) S1931-3128(24)00443-8 | https://doi.org/10.1016/j.chom.2024.11.012
Intestinal E. coli-produced yersiniabactin promotes profibrotic macrophages in Crohn's disease
Ju-Hyun Ahn 1, Marlus da Silva Pedrosa 1, Lacey R. Lopez 1, Taylor N. Tibbs 1, Joanna N. Jeyachandran 1, Emily E. Vignieri 2, Aaron Rothemich 1, Ian Cumming 3, Alexander D. Irmscher 4, Corey J. Haswell 4, William C. Zamboni 4,5, Yen-Rei A. Yu 3,6, Melissa Ellermann 2, Lee A. Denson 7, Janelle C. Arthur 1,5,8,9
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
3Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
4UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
5Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
6Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
7Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
8Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
9Lead contact
Corresponding author : Janelle C. Arthur
1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA
3Department of Pulmonary and Critical Care Medicine, Duke University, Durham, NC 27710, USA
4UNC Advanced Translational Pharmacology and Analytical Chemistry Lab, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
5Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
6Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
7Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
8Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
9Lead contact
Corresponding author : Janelle C. Arthur
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.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-02-12)
- 국외 연구진
- 생명과학 > 미생물학
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