Induced Disruption of the Iron-Regulatory Hormone Hepcidin Inhibits Acute Inflammatory Hypoferraemia
Open accessAbstract
Withdrawal of iron from serum (hypoferraemia) is a conserved innate immune antimicrobial strategy that can withhold this critical nutrient from invading pathogens, impairing their growth. Hepcidin (Hamp1) is the master regulator of iron and its expression is induced by inflammation. Mice lacking Hamp1 from birth rapidly accumulate iron and are susceptible to infection by blood-dwelling siderophilic bacteria such as Vibrio vulnificus. In order to study the innate immune role of hepcidin against a background of normal iron status, we developed a transgenic mouse model of tamoxifen-sensitive conditional Hamp1 deletion (termed iHamp1-KO mice). These mice attain adulthood with an iron status indistinguishable from littermate controls. Hamp1 disruption and the consequent decline of serum hepcidin concentrations occurred within hours of a single tamoxifen dose. We found that the TLR ligands LPS and Pam3CSK4 and heat-killed Brucella abortus caused an equivalent induction of inflammation in control and iHamp1-KO mice. Pam3CSK4 and B. abortus only caused a drop in serum iron in control mice, while hypoferraemia due to LPS was evident but substantially blunted in iHamp1-KO mice. Our results characterise a powerful new model of rapidly inducible hepcidin disruption, and demonstrate the critical contribution of hepcidin to the hypoferraemia of inflammation.
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HAMP is an important mediator to reduce serum iron levels during the APR, so iron is restricted from bacteria in the circulation.
“As HAMP is an important mediator to reduce serum iron levels during the APR, iron is restricted from bacteria in the circulation (Armitage et al., 2016).”
From Iron in infection and immunity (2020) · cites this paper as Armitage et al., 2016
Hamp and Fpn1 are primary mediators of hypoferremia and influence Salmonella-host interactions.
“Hamp and its receptor Fpn1 are primary mediators of the hypoferremia, and thereby influence Salmonella-host interactions (Nairz et al., 2013; Kim et al., 2014; Armitage et al., 2016).”
From Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection (2017) · cites this paper as Armitage et al., 2016
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- Authors
- Armitage, A. E., Lim, P. J., Frost, J. N., Pasricha, S.-R., Soilleux, E. J., Evans, E., Morovat, A., Santos, A., Diaz, R., Biggs, D., Davies, B., Gileadi, U., Robbins, P. A., Lakhal-Littleton, S., & Drakesmith, H.
- Affiliations
- Heart of England NHS Foundation Trust (GB)
- University of Oxford (GB)
- Oxford University Hospitals NHS Trust (GB)
- Centre for Human Genetics (GB)
- National Institute for Health and Care Research (GB)
- Corresponding author
- Drakesmith, Hal
- ORCID
- Venue
- Journal of Innate Immunity
- Publisher
- S. Karger AG
- Published
- 2016
- Volume
- 8
- Issue
- 5
- Pages
- 517-528
- ISSN
- 1662-811X (ISSN-L)
- 1662-8128
- PMC
- PMC5322583
- OpenAlex
- W2462882736
- Cited by
- 20
- References
- 39
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 4
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Innate Immunity (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- Wellcome Trust (090532, 090532/Z/09/Z, 090532/Z/09/)
- British Heart Foundation (090532/Z/09/Z, FS/12/63/29895)
- University of Oxford
- Vifor Pharma
- Animal and Plant Health Agency
- Medical Research Council
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- hepcidin, inflammation, iron regulation, innate immunity, conditional knockout mice, tamoxifen-inducible deletion, lipopolysaccharide, Pam3CSK4, Brucella abortus, Vibrio vulnificus, transgenic mouse model
- MeSH terms
- Animals, Antigens, Bacterial, Brucella abortus, Genotype, Humans, Inflammation, Lipopolysaccharides, Mice, Inbred C57BL, Mice, Knockout, Iron Metabolism Disorders, Models, Animal, Toll-Like Receptors, Mice, Lipopeptides, Hepcidins
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