Low hepcidin accounts for the proinflammatory status associated with iron deficiency

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Systemic iron requirements are met predominantly through the recycling of iron from senescent erythrocytes by macrophages, a process in which the iron exporter ferroportin (Fpn1) is considered to be essential. Yet the role of Fpn1 in macrophage iron recycling and whether it influences innate immune responses are poorly understood in vivo. We inactivated Fpn1 in macrophages by crossing Fpn1-floxed animals with macrophage-targeted LysM-Cre or F4/80-Cre transgenic mice.Macrophage Fpn1 deletion mice were overtly normal; however, they displayed a mild anemia and iron accumulation in splenic, hepatic, and bone marrow macrophages when fed a standard diet. Iron loading was exacerbated after the administration of iron dextran or phenylhydrazine. When Fpn1 LysM/LysM mice were challenged with an iron-deficient diet, they developed a more severe anemia and strikingly higher splenic iron levels than control mice, indicating significantly impaired iron mobilization from macrophages. Because immune responses can be altered by modulating iron status, we also examined the expression of proinflammatory cytokines. We found that expression levels of TNF-␣ and IL-6 were significantly enhanced in Fpn1 LysM/LysM macrophages lacking Fpn1. These studies demonstrate that Fpn1 plays important roles in macrophage iron release in vivo and in modulating innate immune responses. (Blood. 2011;118(7):1912-1922)

Section: Discussionmentioning

confidence: 99%

Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses

Zhang

et al. 2011

196

185

“…As reported previously, 13,14 the total level of hepcidin expression observed after inflammation seems additive to the baseline level, which requires a functional iron-sensing pathway. In contrast to Hamp Ϫ/Ϫ or iron-deprived mice, 31,32 Bmp6 Ϫ/Ϫ mice do not have a proinflammatory condition exacerbated by LPS compared with wild-type mice (supplemental Figure 1). This may be related to their capacity to up-regulate hepcidin in the inflammatory context, which is preserved.…”

Section: Inflammation Up-regulates Hepcidin Independently Of Bmp6mentioning

confidence: 99%

Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling

Besson-Fournier

Latour

Kautz

et al. 2012

161

142

Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin ␤ B -subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma-derived cells and, synergistically with IL-6 and STAT-3 signaling, upregulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation. (Blood. 2012;120(2):431-439) IntroductionAnemia of inflammation develops as a complication of an acute or chronic activation of the immune response. It is particularly common in hospitalized patients and in the elderly and has a negative impact on recovery and survival. 1,2 Most chronic bacterial, fungal, viral, or parasitic infections with systemic manifestations can cause anemia of inflammation, as do rheumatologic disorders, systemic autoimmune disorders, inflammatory bowel disease, chronic kidney diseases, and some malignancies. 3 The limitation of iron supply to erythropoiesis is a major factor in the development of this anemia. Treatment includes administration of erythropoiesis-stimulating agents and intravenous iron. However, iron is rapidly trapped in the macrophage compartment, 4,5 rendering it unavailable for erythropoiesis once the initial iron bolus is incorporated into RBCs and body stores.Anemia of inflammation appears to be caused, at least in part, by the induction of the iron-regulatory hormone hepcidin. [6][7][8] Hepcidin acts by binding to the sole known iron-export channel, ferroportin, which is found on duodenal enterocytes, macrophages, and hepatocytes, the cell types that export iron into plasma. Binding of hepcidin to ferroportin induces its internalization and degradation, 9 which progressively inhibit iron efflux from these cells, leading to hypoferremia. The fundamental mechanisms causing increased hepcidin production by the liver during inflammation are still incompletely understood, but a cross-talk with the pathway through which hepcidin is regulated by iron is not excluded.Iron overload induces the expression of bone morphogenetic protein 6 (BMP6), a member of the TGF-␤ superfamily. Binding of BMP6 to paired serine/thr...

“…Iron parameters such as transferrin saturation, serum iron, liver iron content (LIC), and spleen iron content (SIC) were analyzed as previously described 24,25 and according to the method recommended by Torrance. 26 Briefly, 100 mg of tissue were homogenized with 150 mL water in a FastPrep-24 Instrument (MP Biomedicals, Santa Ana, CA) for 60 seconds at 6 m/s, mixed with a solution of HCl 30%/trichloracetic acid 10% in a final volume of 1.5 mL, and kept overnight at 65°C before performing the colorimetric assay.…”

Section: Analysis Of Hematologic and Iron Parametersmentioning

confidence: 99%

Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice

Nai

Rubio

Campanella

et al. 2016

Self Cite

Key Points• Hyperactivation of the BMP-SMAD pathway blunts EPO-mediated hepcidin inhibition.• Lack of BMP-SMAD pathway inhibition by matriptase-2 abrogates the ERFEmediated hepcidin suppression in response to EPO.Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the