Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice
Open accessAbstract
Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-alpha and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-alpha similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-beta expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-beta, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation.
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Hepcidin deficiency changes tissue iron distribution and depletes macrophages of iron, which could affect innate immune signaling.
“Hepcidin deficiency results in altered tissue iron distribution and iron-depleted macrophages, and this could potentially affect innate immune signaling (Oexle et al., 2003; Wang et al., 2009).”
From Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus (2015) · cites this paper as Wang et al., 2009
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- Authors
- Wang, L., Harrington, L., Trebicka, E., Shi, H. N., Kagan, J. C., Hong, C. C., Lin, H. Y., Babitt, J. L., & Cherayil, B. J.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Boston Children's Hospital (US)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Cherayil, Bobby J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2009-10-05
- Volume
- 119
- Issue
- 11
- Pages
- 3322-8
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2769199
- OpenAlex
- W2167404536
- Cited by
- 162
- References
- 44
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 11 · 2020: 8 · 2019: 14 · 2018: 9 · 2017: 6 · 2016: 7 · 2015: 11 · 2014: 13 · 2013: 10 · 2012: 9
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (R01 071837)
- National Heart, Lung, and Blood Institute (K08HL081535)
- National Institute of Allergy and Infectious Diseases (R00AI072955)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TLR4 signaling, iron homeostasis, hemochromatosis, macrophages, lipopolysaccharide, interferon-beta, TLR2, TLR3, TNF-α, interleukin-6, salmonellosis, enterocolitis, inflammation, iron chelation
- MeSH terms
- Animals, Enterocolitis, Gene Expression Regulation, Hemochromatosis, Homeostasis, Immunity, Innate, Inflammation, Iron, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Salmonella Infections, Signal Transduction, Mice, Knockout, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88
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