Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages
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. Upon infection macrophage...
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| Format: | Article |
| Language: | English |
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Wiley
2014-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2014/140728 |
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| author | Susu M. Zughaier Brandon B. Stauffer Nael A. McCarty |
| author_facet | Susu M. Zughaier Brandon B. Stauffer Nael A. McCarty |
| author_sort | Susu M. Zughaier |
| collection | DOAJ |
| description | 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. 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 have 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 expression, 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. This is the first report to show that inflammation and ER stress downregulate the expression of BDH2 in human THP-1 macrophages. |
| format | Article |
| id | doaj-art-93f2bdc51bcd479f9a2632525ec7d1d4 |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-93f2bdc51bcd479f9a2632525ec7d1d42025-02-03T05:52:33ZengWileyJournal of Immunology Research2314-88612314-71562014-01-01201410.1155/2014/140728140728Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in MacrophagesSusu M. Zughaier0Brandon B. Stauffer1Nael A. McCarty2Department of Microbiology and Immunology, Veterans Affairs Medical Center (VAMC (151-I)), Emory University School of Medicine and Children’s Healthcare of Atlanta, 1670 Clairmont Road, Atlanta, GA 30033, USAEmory-Children’s Center for Cystic Fibrosis and Airways Disease Research, Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA 30322, USAEmory-Children’s Center for Cystic Fibrosis and Airways Disease Research, Division of Pulmonology, Allergy/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA 30322, USAMacrophages 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. 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 have 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 expression, 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. This is the first report to show that inflammation and ER stress downregulate the expression of BDH2 in human THP-1 macrophages.http://dx.doi.org/10.1155/2014/140728 |
| spellingShingle | Susu M. Zughaier Brandon B. Stauffer Nael A. McCarty Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages Journal of Immunology Research |
| title | Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages |
| title_full | Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages |
| title_fullStr | Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages |
| title_full_unstemmed | Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages |
| title_short | Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages |
| title_sort | inflammation and er stress downregulate bdh2 expression and dysregulate intracellular iron in macrophages |
| url | http://dx.doi.org/10.1155/2014/140728 |
| work_keys_str_mv | AT susumzughaier inflammationanderstressdownregulatebdh2expressionanddysregulateintracellularironinmacrophages AT brandonbstauffer inflammationanderstressdownregulatebdh2expressionanddysregulateintracellularironinmacrophages AT naelamccarty inflammationanderstressdownregulatebdh2expressionanddysregulateintracellularironinmacrophages |