Disorders of iron metabolism, either genetically-determined or secondary to other illnesses, are relatively common cllinical problems. Our preliminary studies with Hfe knock-out (KO) mice, a model of human type I hemochromatosis (HH), have revealed that the abnormal iron metabolism in these animals is associated with attenuated inflammatory responses in vivo and in vitro. Individuals with type I HH, as well as Hfe KO mice, have abnormally low circulating levels of the hepatocyte-derived, iron-regulatory peptide hepcidin. As a result, there is a reduction of intra-macrophage iron concentrations accompanied by elevation of serum iron, with the latter leading to pathological deposition of the metal in various tissues. Our results indicate that the decrease of iron within macrophages impairs the ability of these cells to produce TNF1 and IL-6 in response to Gram- negative bacteria or LPS. The abnormality manifests in vivo as a reduction in the severity of Salmonella- induced enterocolitis. In additional studies with wild-type (WT) mice and with mouse models of inflammatory bowel disease (IBD), we found that both infectious and non-infectious forms of colitis are associated with increased expression of hepcidin, and that blocking hepcidin expression reduces the severity of intestinal inflammation. Although increased hepcidin is a well known factor in the anemia of chronic inflammatory states, our experiments suggest that it also contributes to the pathogenesis of inflammation by increasing intra- macrophage iron levels and promoting the expression of pro-inflammatory cytokines. Collectively, our observations indicate that changes in iron metabolism have a significant impact on the inflammatory response and, conversely, that inflammation is associated with alterations in iron metabolism that increase the production of inflammatory mediators. Elucidating the mechanisms responsible for this cross-talk will facilitate the development of anti-inflammatory strategies based on manipulating iron homeostasis. Therefore, we propose to (1) determine the mechanisms by which Hfe deficiency and the associated reduction in hepcidin expression and intra-macrophage iron attenuate intestinal inflammation, (2) elucidate the mechanisms that lead to the increased hepcidin expression and dysregulated iron metabolism that accompany intestinal inflammation, (3) evaluate the effect of a new strategy for inhibiting hepcidin expression on the severity of intestinal inflammation in mouse models of IBD.
This project is based on preliminary studies showing that altered iron homeostasis, specifically decreased expression of the iron-regulatory peptide hepcidin and a consequent reduction of intra-macrophage iron levels, impairs inflammatory responses in vitro and in vivo, and that intestinal inflammation is associated with an increase in hepcidin expression that contributes to the inflammatory process. We will extend these studies to (1) determine the mechanisms by which Hfe deficiency and the associated reduction in hepcidin expression and intra-macrophage iron attenuate intestinal inflammation, (2) elucidate the mechanisms that lead to the increased hepcidin expression and dysregulated iron metabolism that accompany intestinal inflammation, (3) evaluate the effect of a new strategy for inhibiting hepcidin expression on the severity of intestinal inflammation in mouse models of IBD.
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|Shanmugam, Nanda Kumar N; Chen, Kejie; Cherayil, Bobby J (2015) Commensal Bacteria-induced Interleukin 1? (IL-1?) Secreted by Macrophages Up-regulates Hepcidin Expression in Hepatocytes by Activating the Bone Morphogenetic Protein Signaling Pathway. J Biol Chem 290:30637-47|
|Trebicka, Estela; Shanmugam, Nanda Kumar N; Chen, Kejie et al. (2015) Intestinal Inflammation Leads to a Long-lasting Increase in Resistance to Systemic Salmonellosis that Requires Macrophages But Not B or T Lymphocytes at the Time of Pathogen Challenge. Inflamm Bowel Dis 21:2758-65|
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|Shanmugam, Nanda Kumar N; Trebicka, Estela; Fu, Ling-Lin et al. (2014) Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota. J Immunol 193:1398-407|
|Trebicka, Estela; Shanmugam, Nanda Kumar N; Mikhailova, Anastassia et al. (2014) Effect of human immunodeficiency virus infection on plasma bactericidal activity against Salmonella enterica serovar Typhimurium. Clin Vaccine Immunol 21:1437-42|
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