oa Inflammation And Er Stress Downregulate Bdh2 Expression And Dysregulate Intracellular Iron In Macrophages

Altered iron homeostasis is associated with many chronic diseases and characterized by misdistribution of iron that manifests in hypoferremia and iron retention in the reticuloendothelial system. Macrophages play a very important role in host defense and in iron homeostasis by engulfing senescent red blood cells and recycling iron. Hepcidin is the master iron regulating hormone that limits dietary iron absorption from the gut and limits iron egress from macrophages; therefore, upon infection macrophages retain iron to limit its bioavailability which limits bacterial growth. Recently, a short chain butyrate dehydrogenase type 2 (BDH2) protein was reported to contain an iron responsive element and to mediate cellular iron trafficking by catalyzing the synthesis of the mammalian siderophore that binds labile iron; therefore, BDH2 plays a crucial role in intracellular iron homeostasis. However, BDH2 expression and regulation in macrophages has not yet been described. Here we show that LPS-induced inflammation combined with ER stress led to massive BDH2 downregulation, increased the expression of ER stress markers, upregulated hepcidin expression, downregulated ferroportin, caused iron retention in macrophages, and dysregulated cytokine release from macrophages. We also show that ER stress combined with inflammation synergistically upregulated the expression of the iron carrier protein NGAL and the stress-inducible heme degrading enzyme heme oxygenase 1 (HO-1) leading to iron liberation. However, vitamin D treatment prior to LPS exposure restored BDH2 expression. Taken together, the data suggest that inflammation combined with ER stress dysregulated intracellular iron homeostasis in macrophages. This is the first report to show that inflammation and ER stress downregulates the expression of BDH2 in human THP-1 macrophages. A clinical translational study of this finding will be conducted on patients with Alzheimer disease, cystic fibrosis disease and COPD compared to healthy subjects to investigate iron status i.e. anemia of chronic inflammation, iron indexes, inflammation markers (proinflammatory cytokines and chemokines such as IL-6 and MCP-1) and expression of BDH2, hepcidin-ferroprotin axis and intracellular iron retention in peripheral monocytes. Since vitamin D improves iron status, relieves ER stress and restores BDH2 expression we propose to translate our finding in a double blind clinical study where subjects will receive high dose of vitamin D or placebo as therapy to restore altered iron homeostasis.