Differential regulation of iron homeostasis during human macrophage polarized activation
Open accessAbstract
Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN‐γ (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin‐mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions.
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M1 macrophages display high iron retention and low iron export to restrict microenvironmental iron availability, preventing bacterial growth.
“These cells display a high level of iron retention and low iron export to restrict the availability of microenvironmental iron capable of aiding bacterial expansion, thereby preventing the growth of infections [18].”
From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [18]
M2 macrophages consistently express scavenger and mannose receptors (CD206), release anti-inflammatory cytokines such as IL-10, display high iron export aiding tissue remodeling, and encompass subsets including wound healing and regulatory macrophages.
“M2 macrophages consistently express scavenger and mannose receptors (CD206), release anti-inflammatory cytokines such as IL-10 [19], display a high level of iron export aiding in tissue remodeling [18] and encompass a range of different subsets (i.e., M2a, M2b, M2c) including 'wound healing' and 'regulatory macrophages' [20].”
From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [18]
Hydrogen peroxide and superoxide anion modulate IRP-1 activity via kinase/phosphatase signal transduction pathways, resulting in divergent posttranscriptional regulation of IRE-regulated target genes such as TfR and ferritin.
“Moreover, hydrogen peroxide and superoxide anion modulate IRP-1 activity by a rapidly inducible process involving kinase/phosphatase signal transduction pathways resulting in divergent posttranscriptional regulation of IRE-regulated target genes such as transferrin receptor (TfR) and ferritin (178, 179).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [179]
Anti-inflammatory macrophages are predisposed to iron export and the distribution of iron to the extracellular space, whereas iron storage is reduced.
“In contrast, anti-inflammatory macrophages are predisposed to iron export and the distribution of iron to the extracellular space, whereas iron storage is reduced.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [67]
Pro-inflammatory macrophages are prone to iron retention, displaying an iron sequestering phenotype characterized by enhanced iron uptake and storage, but attenuated release.
“Pro-inflammatory macrophages are prone to iron retention. They display an iron sequestering phenotype characterized by enhanced iron uptake and storage, but attenuated release [64,65,66,67].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [67]
The iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo.
“This iron-donating macrophage phenotype was directly linked to enhanced tumor cell proliferation and growth, both in vitro and in vivo [64,66,67,70,71,72].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [67]
The iron-release phenotype is associated with upregulation of the iron exporter FPN, while the iron storage protein FT is downregulated.
“The iron-release phenotype is associated with upregulation of the iron exporter FPN, while the iron storage protein FT is downregulated [67].”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [67]
Regulation of macrophage intracellular iron content by the hepcidin/FPN axis impacts macrophage polarization and presumably resistance to infection.
“Regulation of Mø intracellular Fe content by the hepcidin/FPN axis impacts on Mø polarization and presumably therefore resistance to infection [6,66,67].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [66]
This defense strategy changes cellular iron content, which affects the microbicidal activity of innate immune cells such as macrophages.
“Importantly, this defense strategy modulates cellular Fe content, which impacts on the microbicidal activity of innate immune cells such as macrophages (30, 98, 99).”
From Innate Nutritional Immunity (2018) · cites this paper as [98]
Macrophages associated with tumours might increase iron release in the tumour microenvironment.
“tumour-associated macrophages may promote iron release in the tumour microenvironments40,41.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [41]
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- Authors
- Recalcati, S., Locati, M., Marini, A., Santambrogio, P., Zaninotto, F., De Pizzol, M., Zammataro, L., Girelli, D., & Cairo, G.
- Affiliations
- University of Milan (IT)
- IRCCS Ospedale San Raffaele (IT)
- University of Verona (IT)
- Corresponding author
- Cairo, Gaetano
- ORCID
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2010-03
- Volume
- 40
- Issue
- 3
- Pages
- 824-835
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W2136428555
- Cited by
- 438
- References
- 56
- Citations by year
- 2026: 42 · 2025: 18 · 2024: 30 · 2023: 24 · 2022: 39 · 2021: 44 · 2020: 35 · 2019: 31 · 2018: 24 · 2017: 26 · 2016: 19 · 2015: 20 · 2014: 27 · 2013: 24 · 2012: 14
- FWCI
- 7.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondazione Cariplo
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Keywords
- iron homeostasis, macrophage polarization, M1 macrophages, M2 macrophages, ferroportin, ferritin, heme oxygenase, Th2 cytokines, inflammation, iron chelation, macrophage-conditioned medium, cell proliferation
- MeSH terms
- Adult, Homeostasis, Humans, Iron, Macrophage Activation, Macrophages, Middle Aged, Immunoblotting, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling
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