Cell iron status influences macrophage polarization

Agoro, Rafiou; Taleb, Meriem; Quesniaux, Valérie; Mura, Catherine

doi:10.1371/journal.pone.0196921

Cited by 139 publications

(135 citation statements)

References 63 publications

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“…The clear dampening of Nos2a gene induction in the absence of H-ferritin and in a situation of low intracellular iron level, was also an intriguing observation per se and corroborates a previous observation by Bolisetty et al 19 . Several previous studies showed that treating macrophages with excess iron decreased Nos2a expression and nitrite production upon treatment with IFNG and/or LPS [27][28][29] . We now postulate that these effects were due to increased intracellular oxidative stress rather than to a direct effect of iron.…”

Section: Discussionmentioning

confidence: 95%

“…We now postulate that these effects were due to increased intracellular oxidative stress rather than to a direct effect of iron. Different signalling pathways have been implicated in the relationship between iron and Nos2a expression, including signal transducer and activator of transcription 1 (STAT1) 27 and hypoxia-inducible factor 1-alpha (HIF1A) 30 . The intracellular iron levels, labile iron pool (LIP) and Iron Responsive Proteins (IRP) have also been implicated 31 .…”

Section: Discussionmentioning

confidence: 99%

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H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Mesquita

Silva

Gomes

et al. 2020

Sci Rep

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Macrophages are central cells both in the immune response and in iron homeostasis. Iron is both essential and potentially toxic. Therefore, iron acquisition, transport, storage, and release are tightly regulated, by several important proteins. Cytosolic ferritin is an iron storage protein composed of 24 subunits of either the L-or the H-type chains. H-ferritin differs from L-ferritin in the capacity to oxidize fe 2+ to fe 3+ . In this work, we investigated the role played by H-ferritin in the macrophages' ability to respond to immune stimuli and to deal with exogenously added iron. We used mice with a conditional deletion of the H-ferritin gene in the myeloid lineage to obtain bone marrow-derived macrophages. These macrophages had normal viability and gene expression under basal culture conditions. However, when treated with interferon-gamma and lipopolysaccharide they had a lower activation of Nitric Oxide Synthase 2. Furthermore, H-ferritin-deficient macrophages had a higher sensitivity to ironinduced toxicity. This sensitivity was associated with a lower intracellular iron accumulation but a higher production of reactive oxygen species. These data indicate that H-ferritin modulates macrophage response to immune stimuli and that it plays an essential role in protection against iron-induced oxidative stress and cell death.Since macrophages and iron metabolism are tightly connected and H-ferritin is crucial for iron storage inside the cells, we hypothesized that H-ferritin has a key role in macrophages viability, development, activation, and iron handling. To test this hypothesis, we used mice with a conditional deletion of the H-ferritin gene (Fth1) in the myeloid lineage, generated from the H-ferritin-loxP mice created by Lukas Kuhn and collaborators 17 . We obtained bone marrow-derived macrophages (BMDM) from these mice and found that although in vitro macrophage differentiation proceeded normally, H-ferritin-deficient BMDM had subtle alterations in their response to immune stimulation and a marked increase in susceptibility to oxidative stress and cell death induced by exogenously added iron. Scientific RepoRtS |(2020) 10:3061 | https://doi.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Mesquita

Silva

Gomes

et al. 2020

Sci Rep

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“…PLP is a cofactor in more than 150 enzymatic reactions and may help regulate inflammation by acting in pathways that produce metabolites with immunomodulatory effects [52]. In vitro and in vivo studies show that an iron-rich status promotes an M2-like macrophage phenotype (which is associated with wound healing and tissue repair) and negatively regulates an M1 pro-inflammatory response (such as production of ROS) through reduced NF-kB p65 nuclear translocation [33]. Zinc is an anti-inflammatory agent [8], while copper is important for the production and response of IL-2 to adaptive immune cells and accumulates at the sites of inflammation [2].…”

Section: Inflammatory Responsementioning

confidence: 99%

A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection

2020

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Immune support by micronutrients is historically based on vitamin C deficiency and supplementation in scurvy in early times. It has since been established that the complex, integrated immune system needs multiple specific micronutrients, including vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium, which play vital, often synergistic roles at every stage of the immune response. Adequate amounts are essential to ensure the proper function of physical barriers and immune cells; however, daily micronutrient intakes necessary to support immune function may be higher than current recommended dietary allowances. Certain populations have inadequate dietary micronutrient intakes, and situations with increased requirements (e.g., infection, stress, and pollution) further decrease stores within the body. Several micronutrients may be deficient, and even marginal deficiency may impair immunity. Although contradictory data exist, available evidence indicates that supplementation with multiple micronutrients with immune-supporting roles may modulate immune function and reduce the risk of infection. Micronutrients with the strongest evidence for immune support are vitamins C and D and zinc. Better design of human clinical studies addressing dosage and combinations of micronutrients in different populations are required to substantiate the benefits of micronutrient supplementation against infection.

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“…This antagonism is bidirectional as IFN‐ γ can promote hypoferremia of inflammation by inducing hepcidin expression in macrophages (Sow et al., 2009) and triggering iron uptake by monocytes via increasing their DMT1 (iron import) while decreasing TfR1 and Fpn1 (iron export) (Ludwiczek, Aigner, Theurl, & Weiss, 2003). Aside from favoring the Th2 bias, iron replete condition has also been shown to polarize macrophages toward the M2 subtype in in vivo and in vitro (Agoro, Taleb, Quesniaux, & Mura, 2018). M2 macrophages are noted for having high ferroportin and low ferritin expression to enhance iron release and reduce iron storage respectively (Recalcati et al., 2010).…”

Section: Discussionmentioning

confidence: 99%

Distinct iron homeostasis in C57BL/6 and Balb/c mouse strains

Saha

Xiao

et al. 2020

Physiol Rep

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C57BL/6 (BL6) and Balb/c mice exhibit prototypical Th1‐ and Th2‐dominant immune predispositions, respectively. Iron is a proinflammatory metal ion; however, limited information is documented on the differences in iron homeostasis between BL6 and Balb/c strains. The objective of this study was to investigate the extent to which strain‐level differences in these mice dictates the regulation of iron homeostasis during physiologic and inflammatory conditions. At basal levels, Balb/c mice displayed significantly higher levels of iron in systemic circulation and tissue compared to BL6 mice. Moreover, Balb/c mice had greater iron absorption as indicated by higher gene expressions of duodenal DcytB, DMT1, Fpn, SFT, and Heph. Similarly, hepatic Tf, TfR1, TfR2, and DMT1 expressions were augmented in Balb/c mice. Interestingly, there was no change in hepatic Hamp expression between the two strains, suggesting that the disparity in their maintenance of iron is independent of hepcidin. Additionally, the basal levels of intracellular labile iron pool in Balb/c intestinal epithelial cells, and bone marrow‐derived macrophages and neutrophils, were higher compared to BL6 mice. When mice were challenged with lipopolysaccharide, the acute inflammatory response in BL6 mice was more pronounced than in Balb/c mice, as indicated by the more rapid development of hypoferremia and upregulation of serum IL‐6 and TNF‐α levels in BL6 mice. In conclusion, this study underscores that iron homeostasis is distinct between BL6 and Balb/c strains under both physiologic and inflammatory conditions.

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Cell iron status influences macrophage polarization

Cited by 139 publications

References 63 publications

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection

Distinct iron homeostasis in C57BL/6 and Balb/c mouse strains

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