Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression
Abstract
Hepcidin, a small cationic liver derived peptide, is a master regulator of body iron homeostasis. Cytokines and iron availability have so far been identified as regulators of hepcidin expression. Herein, we investigated the functional role of Kupffer cells for hepcidin expression because of their vicinity to the hepatocytes and their importance for iron recycling via erythrophagocytosis. We investigated C57Bl6 mice and littermates, in which Kupffer cells were eliminated in vivo upon intravenous injection of liposome-encapsulated clodronate. Primary cultures of hepatocytes and Kupffer cells were used to study direct regulatory effects ex vivo. The in vivo depletion of Kupffer cells resulted in a significant increase in liver hepcidin expression, which was paralleled by a significant reduction in serum iron levels. The same pattern of regulation by Kupffer cell depletion was observed upon injection of bacterial lipopolysaccharide into mice and in primary (Hfe -/-) and in secondary iron-overloaded mice. Accordingly, the messenger ribonucleic acid (mRNA) concentrations of the hepcidin iron-sensing molecule hemojuvelin were not significantly changed upon Kupffer cell depletion. When primary hepatocytes were cocultivated with Kupffer cells or stimulated with a Kupffer cell-conditioned medium ex vivo, a significant reduction in hepatocyte hepcidin mRNA expression was observed. Our data suggest that Kupffer cells control body iron homeostasis by exerting negative regulatory signals toward hepcidin expression, which may be primarily referred to the secretion of yet unidentified hepcidin-suppressing molecules by Kupffer cells.
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Culture supernatants from primary Kupffer cells blunted hepcidin production in co-cultured primary Kupffer cells and hepatocytes.
“These findings thus contrast to what has been shown for co-cultured primary Kupffer cells and hepatocytes inasmuch as culture supernatants from primary Kupffer cells blunted hepcidin production [228].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [228]
Kupffer cells dampen hepcidin production in homeostatic conditions but may be required for inflammation-driven hepcidin secretion.
“Interestingly, KC dampen HAMP production in homeostatic conditions but may be required for inflammation-driven HAMP secretion [44, 45].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [44]
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- Authors
- Theurl, M., Theurl, I., Hochegger, K., Obrist, P., Subramaniam, N., van Rooijen, N., Schuemann, K., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- ORCID
- Theurl, Igor
- Venue
- Journal of Molecular Medicine
- Published
- 2008-06-03
- Volume
- 86
- Issue
- 7
- Pages
- 825-835
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W170317777
- Cited by
- 69
- References
- 44
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- American Journal of Hematology
- Faculty of Health
- Funders
- American Regent
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Kupffer cells, hepcidin, iron homeostasis, hepcidin regulation, lipopolysaccharide, iron overload, hemojuvelin, erythrophagocytosis, iron recycling, hepatocytes, Kupffer cell depletion, serum iron
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Iron, Kupffer Cells, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Hepatocytes, Antimicrobial Cationic Peptides, Cell Line, Tumor, Mice, Hepcidins
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