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Mycobacteria-induced anaemia: a molecular approach reveals the involvement of NRAMP1 and lipocalin-2 but not hepcidin

ABSTRACT: Anaemia is a frequent complication of chronic infectious diseases but the exact mechanisms by which it develops remain to be clarified. In the present work, we used a mouse model of mycobacterial infection to study molecular alterations of iron metabolism. We show that four weeks after infection with Mycobacterium avium BALB/c mice exhibit a moderate anaemia, which cannot be explained by elevated hepatic hepcidin mRNA expression. Instead, the mice respond with increased mRNA expression of ferroportin (Slc40a1), ceruloplasmin (Cp), hemopexin (Hpx), heme-oxygenase-1 (Hmox1) and lipocalin-2 (Lcn2). Both the anemia and the mRNA expression changes of iron-related genes are largely absent in C.D2 mice which bear a functional allele of the Nramp1 gene. These data suggest that anaemia due to a chronic infection with M. avium develops independently of elevated hepcidin expression and possibly involves ferroportin and/or lipocalin-2.

ORGANISM(S): Mus musculus

PROVIDER: GSE20024 | GEO | 2011/08/01

SECONDARY ACCESSION(S): PRJNA124105

REPOSITORIES: GEO

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Mycobacteria-induced anaemia: a molecular approach reveals the involvement of NRAMP1 and lipocalin-2 but not hepcidin

Project description:Anaemia is a frequent complication of chronic infectious diseases but the exact mechanisms by which it develops remain to be clarified. In the present work, we used a mouse model of mycobacterial infection to study molecular alterations of iron metabolism. We show that four weeks after infection with Mycobacterium avium BALB/c mice exhibit a moderate anaemia, which cannot be explained by elevated hepatic hepcidin mRNA expression. Instead, the mice respond with increased mRNA expression of ferroportin (Slc40a1), ceruloplasmin (Cp), hemopexin (Hpx), heme-oxygenase-1 (Hmox1) and lipocalin-2 (Lcn2). Both the anemia and the mRNA expression changes of iron-related genes are largely absent in C.D2 mice which bear a functional allele of the Nramp1 gene. These data suggest that anaemia due to a chronic infection with M. avium develops independently of elevated hepcidin expression and possibly involves ferroportin and/or lipocalin-2. A pool of five mice total RNAs for each condition was used in the experiments. Each two channel chip experiment was done in duplicates with swapped dyes.

2011-07-31 | E-GEOD-20024 | biostudies-arrayexpress

Mus musculus

Project description:Mycobacteria-induced anaemia: a molecular approach reveals the involvement of NRAMP1 and lipocalin-2 but not hepcidin

| PRJNA124105 | ENA

A Liver Hepcidin-Intestinal HIF-2α Axis Regulates Iron Absorption During Systemic Iron Deficiency, Hypoxia and Hemochromatosis

Project description:Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin (Hamp), a hepatic-derived hormone that controls iron mobilization through its molecular target, ferroportin (FPN), the only known mammalian iron exporter. Here, we took a transcriptomic approach to to compare the duodenal transcriptome during systemic iron demand to that of hepcidin-deficiency iron overload. Hampfl/fl (control) and AlbCreERT2;Hampfl/fl mice were placed on iron-replete and low-iron diets and were sacrificed two weeks following tamoxifen treatment. Duodenum RNA expression was compared across genotypes and across iron-replete and low iron diets.

2018-12-12 | E-MTAB-7329 | biostudies-arrayexpress

Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing

Project description:Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the significance or regulation of these changes remains unclear. Here we report that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the intestine following experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified that conventional dendritic cells (DCs) are a source of hepcidin that is induced by microbial stimulation, prominent in the inflamed intestine of humans, and essential for tissue repair. Mechanistically, DC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and subsequently facilitated intestinal repair. Collectively, these results identify a novel pathway whereby DC-derived hepcidin promotes mucosal healing in the intestine via nutritional immunity.

2020-04-15 | GSE139371 | GEO

Bulk RNA-seq of the human malaria parasite Plasmodium falciparum 3D7 cultured under different iron conditions

Project description:Background: Host iron deficiency is protective against severe malaria as the human malaria parasite Plasmodium falciparum depends on free iron from its host to proliferate. Due to the absence of transferrin, ferritin, ferroportin, and a functional heme oxygenase, the parasite’s essential pathways of iron acquisition, storage, export, and detoxification differ from those in humans and may thus be excellent targets for therapeutic development. However, the proteins involved in these processes in P. falciparum remain largely unknown. Experimental design: To identify iron-regulated mechanisms and putative iron transporters in the human malaria parasite Plasmodium falciparum 3D7, we carried out whole-transcriptome profiling using bulk RNA-sequencing. The parasites were cultured either using erythrocytes from a donors with high, medium (healthy) or low iron status (experiment 1); or with red blood cells from another healthy donor in the presence or absence of 0.7 µM hepcidin, a specific ferroportin inhibitor and iron-regulatory hormone (experiment 2). This concentration of hepcidin was reported to reduce binding of ferrous iron to ferroportin by 50% in vitro (39). Samples from three biological replicates each were harvested at the ring and trophozoite stage (6 – 9 and 26 – 29 hours post invasion, hpi) during the second intra-erythrocytic developmental cycle under the conditions specified.

2024-04-08 | E-MTAB-13411 | biostudies-arrayexpress

Gene signature profiles in lung tisses of wild type mice or Nrf2 deficient mice infected with my nontuberculous mycobacteria

Project description:Background. Nuclear erythroid 2 p45-related factor 2 (Nrf2) regulates the expression of antioxidant and detoxification genes and are thought to be important in protection against intracellular pathogens. The aim of this study was to determine the role of Nrf2 in the host defense against Mycobacterium avium complex (MAC) infection in mice. Methods. Wild-type mice and Nrf2-deficient mice were infected with MAC via intranasal inoculation with 1x107 CFU of Mycobacterium avium subsp. hominissuis. At 2 months after infection, the bronchoalveolar lavage fluid, lung tissues were collected, then, comprehensive transcriptome analysis in the lungs was performed by RNA-seq. Results. Nrf2-deficient mice were highly susceptible to MAC, compared with wild-type mice. There was no significant changes between genotypes in the level of oxidative stress. In addition, the expression of genes related to Th1 immunity and the proportion of Th1 cells were not changed between genotypes. Comprehensive transcriptome analysis showed that the expression of Nramp1 was much lower in the infected lungs of Nrf2-deficient mice than those of Wild-type mice. The expression of Nramp1 was also much lower in the infected alveolar macrophages of Nrf2-deficient mice than those of Wild-type mice. The result of electron microscopy showed that many infected alveolar macrophages from Nrf2-deficient mice were found to contain a large number of intracellular MAC bacteria compare to alveolar macrophages from wild-type mice, due to inhibition of phagolysosome fusion. Conclusions. This study identified that the Nramp1 regulated by Nrf2 is essential in defining the outcome of MAC disease. Nrf2 is a critical determinant for host resistance to MAC infection as a regulator for the expression of Nramp1.

2020-12-30 | GSE144268 | GEO

A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice

Project description:Tmprss6 is the master inhibitor of hepcidin and its inactivation causes iron refractory iron deficiency anemia both in human and in mice. Mice with iron deficiency anemia (IDA)-low hepcidin show a pro-inflammatory response that is blunted in iron deficienct-high hepcidin Tmprss6 null mice. We investigated the transcriptional response associated with chronic hepcidin overexpression by comparing whole genome transcription profiling of the liver of Tmprss6 KO mice and IDA animals, irrespective of iron deficiency.

2013-10-09 | GSE46287 | GEO

A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice

2013-10-09 | E-GEOD-46287 | biostudies-arrayexpress

Transcription profiling of mouse hepatocytes reinfected with Plasmodium berghei

Project description:We show that an ongoing malaria blood stage infection impairs the establishment of Plasmodium sporozoites in hepatocytes and that secondary infections can only be established after a previous infection has been cleared from circulation. Using control mice, mice infected with sporozoites only, mice infected by iRBCs only or mice reinfected, we show that this impairment is not due to an effect of the acquired host immune response or to a decrease in host cell survival. Instead, an ongoing blood stage infection leads to a significant increase in the expression of hepcidin, a peptide hormone that is secreted by the liver and controls body iron homeostasis. A rapid increase of hepcidin levels during blood stage infection causes sequestration of iron in storage forms within cells of reticuloendothelial system decreasing its availability in hepatocytes, where it is required for Plasmodium sporozoite establishment.

2010-11-01 | E-TABM-839 | biostudies-arrayexpress

3 Week IV Study of RGMC Ab in Female Sprague Dawley Rats

Project description:High levels of hepcidin, the main regulator of systemic iron metabolism leads to various diseases. Targeting hepcidin and lowering its concentration is a possible form of intervention in order to treat these diseases. High turnover rate of hepcidin is a major drawback of therapies directly targeting this peptide. We developed two monoclonal antibodies (mAbs) ABT-207 and h5F9-AM8 which inhibit hemojuvelin also known as repulsive guidance molecule c (RGMc) and downregulate hepcidin. After a single application of these antibodies hepcidin expression in liver and its concentration in serum were reduced. Serum iron increased for several weeks. The RGMc antibodies show a pronounced dose response relationship in rats with h5F9-AM8 having an IC50 (UIBC) of ~80 fold higher than ABT-207. When hepcidin levels were downregulated iron deposition in the liver was visible histologically one week post application. The anitbody-mediated iron deposition was not associated with any toxicologically relevant effect at the doses and timepoints evaluate. Iron depositions seen after 14 weekly treatments with ABT-207 were partially reversible in rats and in cynomolgus monkeys. Due to their long-lasting effects and excellent safety profile, both RGMc-blocking antibodies ABT-207 and h5F9-AM8 are favorable clinical candidates for diseases characterized by high serum hepcidin levels like anemia of chronic disease.

2014-11-14 | GSE63200 | GEO

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