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

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          Abstract

          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.

          Abstract

          Relative to C57BL/6 mice (BL6), Balb/c mice harbor more circulating, tissue and labile iron pool (LIP), which correlates with their generally heightened expression of key iron‐regulatory proteins like divalent metal transporter 1 (DMT1) andferroportin. Accordingly, such strain‐level differences in iron homeostasis could explain the dissimilar degree of developing pro‐inflammatory responses, followed by hypoferremia, in response to inflammatory challenge like lipopolysaccharides (LPS), which occurs more rapidly in BL6 mice than Balb/c mice.

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          Most cited references45

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          Microsomal lipid peroxidation.

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            Ironing out Ferroportin.

            Maintaining physiologic iron concentrations in tissues is critical for metabolism and host defense. Iron absorption in the duodenum, recycling of iron from senescent erythrocytes, and iron mobilization from storage in macrophages and hepatocytes constitute the major iron flows into plasma for distribution to tissues, predominantly for erythropoiesis. All iron transfer to plasma occurs through the iron exporter ferroportin. The concentration of functional membrane-associated ferroportin is controlled by its ligand, the iron-regulatory hormone hepcidin, and fine-tuned by regulatory mechanisms serving iron homeostasis, oxygen utilization, host defense, and erythropoiesis. Fundamental questions about the structure and biology of ferroportin remain to be answered.
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              Regulation of iron metabolism by hepcidin.

              Hepcidin, a peptide hormone made in the liver, is the principal regulator of systemic iron homeostasis. Hepcidin controls plasma iron concentration and tissue distribution of iron by inhibiting intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of ferroportin, the sole known cellular iron exporter. Synthesis of hepcidin is homeostatically increased by iron loading and decreased by anemia and hypoxia. Hepcidin is also elevated during infections and inflammation, causing a decrease in serum iron levels and contributing to the development of anemia of inflammation, probably as a host defense mechanism to limit the availability of iron to invading microorganisms. At the opposite side of the spectrum, hepcidin deficiency appears to be the ultimate cause of most forms of hemochromatosis, either due to mutations in the hepcidin gene itself or due to mutations in the regulators of hepcidin synthesis. The emergence of hepcidin as the pathogenic factor in most systemic iron disorders should provide important opportunities for improving their diagnosis and treatment.
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                Author and article information

                Contributors
                matamvijay.kumar@utoledo.edu
                Journal
                Physiol Rep
                Physiol Rep
                10.1002/(ISSN)2051-817X
                PHY2
                physreports
                Physiological Reports
                John Wiley and Sons Inc. (Hoboken )
                2051-817X
                08 May 2020
                May 2020
                : 8
                : 9 ( doiID: 10.14814/phy2.v8.9 )
                : e14441
                Affiliations
                [ 1 ] Department of Physiology & Pharmacology University of Toledo College of Medicine and Life Sciences Toledo OH USA
                [ 2 ] Center for Systems Biology Massachusetts General Hospital Harvard Medical School Boston MA USA
                [ 3 ] Department of Nutritional Sciences The Pennsylvania State University University Park PA USA
                [ 4 ] Department of Medical Microbiology & Immunology University of Toledo College of Medicine and Life Sciences Toledo OH USA
                Author notes
                [*] [* ] Correspondence

                Matam Vijay‐Kumar, Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, 3000 Transverse Dr, Mail Stop 1008, Toledo, OH 43614 USA.

                Email: matamvijay.kumar@ 123456utoledo.edu

                Author information
                https://orcid.org/0000-0002-8732-0167
                Article
                PHY214441
                10.14814/phy2.14441
                7210116
                32385968
                2723d378-3c67-48f6-89f5-782f2f12b7eb
                © 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 March 2020
                : 18 April 2020
                : 20 April 2020
                Page count
                Figures: 6, Tables: 0, Pages: 14, Words: 8281
                Funding
                Funded by: National Institutes of Health (NIH) , open-funder-registry 10.13039/100000002;
                Award ID: R01 CA219144
                Funded by: Crohn's and Colitis Foundation of America , open-funder-registry 10.13039/100001063;
                Award ID: 522820
                Categories
                Cellular and Molecular Physiology
                Metabolism and Regulation
                Original Research
                Original Research
                Custom metadata
                2.0
                May 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:08.05.2020

                ferroportin,hepcidin,hypoferremia of inflammation,innate immunity,labile iron pool

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