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. IntroductionA dysregulated iron homeostasis is a cornerstone of acute and chronic inflammatory processes involving cell-mediated immunity and frequently leads to the development of anemia, termed as anemia of chronic disease (ACD), or anemia of inflammation. 1,2 ACD is a multifactorial disease, where immune mechanisms play key pathogenetic roles. These include cytokine-mediated suppression of erythropoiesis, 3,4 a blunted erythropoietin response, [5][6][7] and an increased iron accumulation in and a defective iron recycling from the reticuloendothelial system. [8][9][10][11][12][13] The liver-derived acute phase protein hepcidin, which is induced by cytokines and iron, plays a key role in this concert. 14,15 It causes anemia when overexpressed, 16,17 whereas hepcidin mutations lead to hepatic iron overload, 18,19 which can be referred to its regulatory effects on cellular iron efflux. This is exerted after binding of hepcidin to the only known cellular iron exporter ferroportin, [20][21][22] leading to ferroportin internalization and blockade of duodenal iron absorption and macrophage iron recycling. 23 Because hepcidin expression is induced by inflammatory stimuli, including interleukin-6 (IL-6) or lipopolysaccharide (LPS), [24][25][26][27][28][29] an increased expression of this acute phase protein has been found to be associated with macrophage iron retention in ACD patients. 30,31 In addition, hepcidinindependent inhibition of ferroportin mRNA expression by inflammatory cytokines also contributes to macrophage iron rete...

SummaryIn being both, a modifier of cellular immune effector pathways and an essential nutrient for microbes, iron is a critical determinant in host-pathogen interaction. Here, we investigated the metabolic changes of macrophage iron homeostasis and immune function following the infection of RAW264.7 murine macrophages with Salmonella typhimurium. We observed an enhanced expression of the principal iron export protein, ferroportin 1, and a subsequent increase of iron efflux in Salmonella-infected phagocytes. In parallel, the expression of haem oxygenase 1 and of the siderophore-binding peptide lipocalin 2 was markedly enhanced following pathogen entry. Collectively, these modulations reduced both the cytoplasmatic labile iron and the ferritin storage iron pool within macrophages, thus restricting the acquisition of iron by intramacrophage Salmonella. Correspondingly, limitation of macrophage iron decreased microbial survival, whereas iron supplementation impaired immune response pathways in Salmonella-infected macrophages (nitric oxide formation and tumour necrosis factor-a production) and promoted intracellular bacterial proliferation. Our findings suggest that the enhancement of ferroportin 1-mediated iron efflux, the upregulation of the haem-degrading enzyme haem oxygenase 1 and the induction of lipocalin 2 following infection concordantly aim at withholding iron from intracellular S. typhimurium and to increase antimicrobial immune effector pathways thus limiting pathogen proliferation.

Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1 (DMT-1). DMT-1 mediates intracellular iron transport during the transferrin cycle and apical iron absorption in the duodenum. Its additional functions in iron handling in the kidney and liver are less well understood. We show that the L-type calcium channel blocker nifedipine increases DMT-1-mediated cellular iron transport 10- to 100-fold at concentrations between 1 and 100 microM. Mechanistically, nifedipine causes this effect by prolonging the iron-transporting activity of DMT-1. We show that nifedipine mobilizes iron from the liver of mice with primary and secondary iron overload and enhances urinary iron excretion. Modulation of DMT-1 function by L-type calcium channel blockers emerges as a new pharmacological therapy for the treatment of iron overload disorders.

In a search for spectral parameters that can be used to distinguish and to model fricatives, spectral moments, dynamic amplitude, and slope above maximum amplitude were computed for a fricative corpus including sustained fricatives at dierent eort levels, and fricatives in vowel context. Moments varied signicantly by frequency range used in computation. M3 appeared to vary the least across fricative, contrasting with Forrest et al.'s 1988 study. Dynamic amplitude separated sibilants and non-sibilants, as predicted; slope above the maximum amplitude varied signicantly with eort level.

Our results show that exposure to VOCs - at concentrations commonly found in indoor environments - can damage the epidermal barrier and enhance the adverse effect of Der p 1 on sensitized subjects with AE. These findings may contribute to a better understanding of the mechanisms underlying the increase in prevalence and exacerbation of AE.