Autocrine formation of hepcidin induces iron retention in human monocytes
Abstract
Hepcidin, a master regulator of iron homeostasis, is produced in small amounts by inflammatory monocytes/macrophages. Chronic immune activation leads to iron retention within monocytes/macrophages and the development of anemia of chronic disease (ACD). We questioned whether monocyte-derived hepcidin exerts autocrine regulation toward cellular iron metabolism. Monocyte hepcidin mRNA expression was significantly induced within 3 hours after stimulation with LPS or IL-6, and hepcidin mRNA expression was significantly higher in monocytes of ACD patients than in controls. In ACD patients, monocyte hepcidin mRNA levels were significantly correlated to serum IL-6 concentrations, and increased monocyte hepcidin mRNA levels were associated with decreased expression of the iron exporter ferroportin and iron retention in these cells. Transient transfection experiments using a ferroportin/EmGFP fusion protein construct demonstrated that LPS inducible hepcidin expression in THP-1 monocytes resulted in internalization and degradation of ferroportin. Transfection of monocytes with siRNA directed against hepcidin almost fully reversed this lipopolysaccharide-mediated effect. Using ferroportin mutation constructs, we found that ferroportin is mainly targeted by hepcidin when expressed on the cell surface. Our results suggest that ferroportin expression in inflammatory monocytes is negatively affected by autocrine formation of hepcidin, thus contributing to iron sequestration within monocytes as found in ACD.
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Macrophages produce minute amounts of hepcidin in response to inflammatory stimuli such as IL-6 or LPS, thereby blocking iron export in an autocrine fashion.
“Moreover, macrophages produce minute amounts of hepcidin in response to inflammatory stimuli such as IL-6 or LPS thereby blocking iron export in an autocrine fashion (Peyssonnaux et al., 2006; Theurl et al., 2008), which is meant to result from a nutritional immune strategy of the body to reduce the availability of iron for extracellular pathogens (Figure 1).”
From Iron at the interface of immunity and infection (2014) · cites this paper as Theurl et al., 2008
LPS stimulates macrophages to produce HAMP themselves, which reduces FPN1-mediated iron export as an autocrine regulator.
“LPS stimulates macrophages to produce HAMP themselves, which reduces FPN1-mediated iron export as autocrine regulator (Peyssonnaux et al., 2006;Theurl et al., 2008).”
From Iron in infection and immunity (2020) · cites this paper as Theurl et al., 2008
Exposure of macrophages to bacteria, the bacterial wall constituent LPS, and Toll-like receptor agonists results in induction of hepcidin, the major inhibitor of iron export from macrophages.
“exposure of macrophages to bacteria (53), the bacterial wall constituent LPS, and Toll-like receptor agonists (54), all occurring in CVUs (55, 56), result in the induction of hepcidin (57), the major inhibitor of iron export from macrophages.”
From An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice (2011) · cites this paper as [54]
Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and anemia of inflammation in the presence of iron-replete macrophages.
“Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane-mia of inflammation in the presence of iron-replete macrophages.”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [55]
Macrophages produce hepcidin in inflammation, potentiating the systemic effect on iron sequestration.
“Macrophages produce hepcidin in inflammation, potentiating the systemic effect on iron sequestration.55”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [55]
Macrophages produce minute amounts of hepcidin in response to LPS or IL-6, which targets autocrine ferroportin, blocking iron egress to limit iron access to extracellular microbes.
“Moreover, MΦs produce minute amounts of hepcidin in response to challenge with LPS or IL-6, which targets in an autocrine fashion ferroportin exposed on the cell surface, thereby resulting in blockage of iron egress to rapidly limit iron access to extracellular microbes (195, 196).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [195]
Activated macrophages can produce minute amounts of hepcidin in response to bacterial lipopolysaccharide or cytokines, targeting FPN for proteolytic degradation.
“Activated Mø can produce minute amounts of hepcidin in response to bacterial lipopolysaccharide (LPS) or cytokines, targeting FPN for proteolytic degradation [109,110].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [110]
Macrophages form hepcidin autocrine, an immediate mechanism to down-regulate FPN1 at infection sites and prevent cellular iron egress to feed pathogens.
“This is also in a line with the observation of autocrine formation of hepcidin by macrophage which is an immediate mechanism to down-regulate FPN1 expression at sites of infection and to prevent cellular iron egress to feed pathogens [170,171].”
From Iron in immune cell function and host defense (2021) · cites this paper as [171]
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- Authors
- Theurl, I., Theurl, M., Seifert, M., Mair, S., Nairz, M., Rumpold, H., Zoller, H., Bellmann-Weiler, R., Niederegger, H., Talasz, H., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- Departments ofGeneral Internal Medicine,
- Hematology and Oncology, and
- Tyrolean Cancer Research Institute (AT)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-02-15
- Volume
- 111
- Issue
- 4
- Pages
- 2392-2399
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1965254560
- Cited by
- 275
- References
- 54
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 7 · 2023: 6 · 2022: 15 · 2021: 12 · 2020: 14 · 2019: 14 · 2018: 17 · 2017: 12 · 2016: 13 · 2015: 18 · 2014: 21 · 2013: 17 · 2012: 20
- FWCI
- 12.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- 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
- hepcidin, autocrine regulation, iron homeostasis, iron retention, monocytes, ferroportin, anemia of chronic disease, inflammation, lipopolysaccharide, interleukin-6, THP-1 cells, iron export
- MeSH terms
- Anemia, C-Reactive Protein, Chronic Disease, Female, Homeostasis, Humans, Iron, Male, Monocytes, RNA, Messenger, Antimicrobial Cationic Peptides, Hepcidins
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