Attenuated Inflammatory Responses in Hemochromatosis Reveal a Role for Iron in the Regulation of Macrophage Cytokine Translation

Wang, Lijian; Johnson, Erin E.; Shi, Hai Ning; Walker, W. Allan; Wessling‐Resnick, Marianne; Cherayil, Bobby J.

doi:10.4049/jimmunol.181.4.2723

Cited by 146 publications

(178 citation statements)

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“…The first is that iron influences the distinct phenotypical heterogeneity of the two macrophage populations in terms of cytokine production. A study of inflammatory responses in a murine model of hemochromatosis has shown that low intracellular iron levels in macrophages of mutant mice impair the TLR4-activated signalling pathway [49], the translation of IL-6, TNF-a [50], and consequently attenuate the inflammatory response. In line with this finding, it has also been found that the synthesis of these cytokines in M2 macrophages is less than in M1 macrophages [25], and the capacity of some bacteria to reprogram macrophages toward an M2 profile is associated with the persistence of pathogens in tissues and the chronic evolution of infectious diseases [51].…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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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-c (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. Key words: Immune system . Iron . Polarized macrophages IntroductionMacrophages play a critical role in body iron homeostasis by recovering iron from old red blood cells and returning it to the circulation for binding to transferrin, which delivers the metal to the cells that need it for various functions, thus contributing more than 80% to daily iron turnover [1][2][3].Iron retention in the reticuloendothelial system is the main response of body iron homeostasis to inflammation and is regarded as a host's attempt to withhold iron from the invading pathogens [4]. This restricts iron availability for erythroid progenitor cells and may contribute toward causing the common condition of inflammation-related anaemia [1,5,6]. Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. O...

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Section: Discussionmentioning

confidence: 99%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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“…These mice have relatively low iron levels in their macrophages and the cells showed an impaired TLR4, but not TLR3, response. 41 The other site where iron deficiency could affect hepcidin expression is in hepatocytes. We demonstrated that pre-treatment of the hepatoma cell line HuH7 with the iron chelator desferrioxamine led to decreased hepcidin levels in response to IL-6 compared to cells treated with IL-6 only.…”

Section: Il-6/gapdhmentioning

confidence: 99%

Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide

Darshan¹,

Frazer²,

Wilkins³

et al. 2010

Haematologica

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BackgroundExpression of the key iron regulatory hormone hepcidin is increased by some stimuli (iron loading, inflammation) but decreased by others (increased erythropoiesis, iron deficiency). We investigated the response of hepcidin to increased erythropoiesis and iron deficiency in the presence of an acute inflammation to assess the relative strengths of these stimuli. Design and MethodsSprague-Dawley rats were maintained on control or iron-deficient diets and treated with lipopolysaccharide to induce inflammation or phenylhydrazine to stimulate erythropoiesis. The levels of Hamp, IL-6 and a2m mRNA were determined by qualitative real-time polymerase chain reaction and those of serum interleukin-6 and tumor necrosis factor-a were measured by enzyme-linked immunosorbent assay. Cultured RAW264.7 and HuH7 cells were used in associated studies. ResultsThe increase in hepatic hepcidin levels induced by lipopolysaccharide was not affected by phenylhydrazine treatment but was blunted by iron deficiency. Lipopolysaccharide-treated iron-deficient animals also showed lower liver a2m mRNA and reduced serum interleukin-6 and tumor necrosis factor-a, suggesting a more generalized effect of iron deficiency. Similarly, RAW 264.7 cells treated with iron chelators and then stimulated with lipopolysaccharide showed lower IL-6 mRNA than cells treated with lipopolysaccharide alone. Huh7 cells treated with an iron chelator showed a blunted hepcidin response to interleukin-6, suggesting that the response of hepatic parenchymal cells to inflammatory cytokines may also be iron-dependent. ConclusionsIn any one physiological situation, net hepcidin levels are determined by the relative strengths of competing stimuli. The ability of severe iron deficiency to blunt the response to lipopolysaccharide of both hepcidin and other markers of inflammation suggests that adequate iron levels are necessary for a full acute phase response.Key words: hepcidin, a2m, erythropoiesis, iron, inflammation. Hamp and pro-inflammatory cytokines to lipopolysaccharide. Haematologica 2010;95(10):1660-1667. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Darshan D, Frazer DM, Wilkins SJ, and Anderson GJ. Severe iron deficiency blunts the response of the iron regulatory gene Severe iron deficiency blunts the response of the iron regulatory gene

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“…От содержания железа в организме зависят процессы адаптации, биоритмы обменных про-цессов, состояние иммунной системы [10,14].…”

Section: Introductionunclassified

Administration of Iron(iii)-Hydroxide Polymaltose in the Treatment of Iron Deficiency Anemia in Children

Ловцова¹

2017

Med. sov.

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Attenuated Inflammatory Responses in Hemochromatosis Reveal a Role for Iron in the Regulation of Macrophage Cytokine Translation

Cited by 146 publications

References 58 publications

Differential regulation of iron homeostasis during human macrophage polarized activation

Differential regulation of iron homeostasis during human macrophage polarized activation

Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide

Administration of Iron(iii)-Hydroxide Polymaltose in the Treatment of Iron Deficiency Anemia in Children

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