Abstract
Iron homeostasis is tightly regulated to provide virtually all cells in the body, particularly red blood cells, with this essential element while defending against its toxicity. The peptide hormone hepcidin is central to the control of the amount of iron absorbed from the diet and iron recycling from macrophages. Previously, we have shown that hepcidin induction in macrophages following Toll-like receptor (TLR) stimulation depends on the presence of myeloid differentiation primary response gene 88 (MyD88). In this study, we analyzed the regulation of iron metabolism in MyD88−/− mice to further investigate MyD88 involvement in iron sensing and hepcidin induction. We show that mice lacking MyD88 accumulate significantly more iron in their livers than wild-type counterparts in response to dietary iron loading as they are unable to appropriately control hepcidin levels. The defect was associated with inappropriately low levels of Smad4 protein and Smad1/5/8 phosphorylation in liver samples found in the MyD88−/− mice compared to wild-type mice. In conclusion, our results reveal a previously unknown link between MyD88 and iron homeostasis, and provide new insights into the regulation of hepcidin through the iron-sensing pathway.
Highlights
Iron homeostasis in mammals is tightly regulated to meet body requirements while preventing iron toxicity, as iron can participate in the generation of harmful free radicals (Hentze et al, 2004; Sheftel et al, 2011)
The contribution of Toll-like receptor (TLR)/myeloid differentiation primary response gene 88 (MyD88) signaling for hepcidin expression through the inflammatory pathway has been further demonstrated using a variety of cellular and animal models (Wang et al, 2009; Xiong et al, 2016; Lee et al, 2017). Since both the iron-sensing pathway and inflammatory pathways reveal overlap in hepcidin induction when converging at SMAD1/5/8 phosphorylation and SMAD4 binding, we investigated the potential role of MyD88 in iron sensing by analyzing iron metabolism in MyD88-deficient mice (MyD88−/−)
We have previously reported that mice deficient in MyD88, unlike Trif-deficient mice, are unable to maintain LPS-induced, acute hypoferremic response as they fail to divert iron from the circulation into the spleen (Layoun et al, 2012)
Summary
Iron homeostasis in mammals is tightly regulated to meet body requirements while preventing iron toxicity, as iron can participate in the generation of harmful free radicals (Hentze et al, 2004; Sheftel et al, 2011). Most of this regulation takes place at the level of intestinal iron absorption, which is negatively controlled by levels of the peptide hormone hepcidin, encoded by the HAMP gene (Ganz and Nemeth, 2012). Erythropoietic activity, hypoxia, host defense, and multiple signals reflecting systemic iron stores and circulating levels converge to regulate hepcidin production, mostly in the liver, and affect body iron homeostasis (Huang et al, 2009).
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