Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage
Sepsis, the most common cause of acute kidney injury, remains a major socioeconomic burden. A dysregulated immune response leads to progressive organ dysfunction. Although numerous inflammatory pathways were described, most are still vague and need to be studied in terms of the mechanisms to improve...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2025.1430946/full |
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| author | Mira Hanna Ahmed M. A. Akabawy Mohamed Mansour Khalifa Mohamed Mansour Khalifa Marawan Abd Elbaset Reda Abdelnasser Imam Hanan Seddiek |
| author_facet | Mira Hanna Ahmed M. A. Akabawy Mohamed Mansour Khalifa Mohamed Mansour Khalifa Marawan Abd Elbaset Reda Abdelnasser Imam Hanan Seddiek |
| author_sort | Mira Hanna |
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| description | Sepsis, the most common cause of acute kidney injury, remains a major socioeconomic burden. A dysregulated immune response leads to progressive organ dysfunction. Although numerous inflammatory pathways were described, most are still vague and need to be studied in terms of the mechanisms to improve the therapeutic intervention. We tackled the relationship between intracellular iron overload and macrophage polarization within 6, 24, and 72 h of sepsis induction. In our study, sepsis-induced kidney injury was caused by using the cecal ligation and puncture (CLP) model. Our results indicated severe renal tissue damage with a progressive increase in serum BUN and creatinine with architectural tissue damage and positive PAS staining. There was increased expression of CD8+ CD68+ M1 macrophage markers with upregulation of iNOS and co-expression of CD163+. Alternatively, Arg1+ Fizz1+ M2 macrophage markers were downregulated with increased iNOS/Arg1 ratio. TFR1, cubilin, and DMT1, as iron transport systems, were increased compared to sham but were significant after 72 h, while ZIP8 showed no significant change. There was a correlation between iron overload and M1 macrophage polarization with CD163+ phenotype, together with fibrotic changes. The intracellular iron overload with downregulation of ferritin was strongly related to macrophage polarization that was exaggerated at 72 h. Finally, early introduced therapy to target free iron during sepsis is a proposed novel solution for protecting the renal tissue from acute injury due to macrophage activation that may end up with chronic kidney injury, if not mortality. |
| format | Article |
| id | doaj-art-d0f89c29294a4a9bbf3039752c434d03 |
| institution | Kabale University |
| issn | 1664-042X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj-art-d0f89c29294a4a9bbf3039752c434d032025-01-30T06:22:14ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2025-01-011610.3389/fphys.2025.14309461430946Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damageMira Hanna0Ahmed M. A. Akabawy1Mohamed Mansour Khalifa2Mohamed Mansour Khalifa3Marawan Abd Elbaset4Reda Abdelnasser Imam5Hanan Seddiek6Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, Cairo, EgyptDepartment of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, EgyptDepartment of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, Cairo, EgyptDepartment of Medical Physiology, College of Medicine, King Saud University, Riyadh, Saudi ArabiaDepartment of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, EgyptDepartment of Anatomy and Embryology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, Cairo, EgyptDepartment of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, Cairo, EgyptSepsis, the most common cause of acute kidney injury, remains a major socioeconomic burden. A dysregulated immune response leads to progressive organ dysfunction. Although numerous inflammatory pathways were described, most are still vague and need to be studied in terms of the mechanisms to improve the therapeutic intervention. We tackled the relationship between intracellular iron overload and macrophage polarization within 6, 24, and 72 h of sepsis induction. In our study, sepsis-induced kidney injury was caused by using the cecal ligation and puncture (CLP) model. Our results indicated severe renal tissue damage with a progressive increase in serum BUN and creatinine with architectural tissue damage and positive PAS staining. There was increased expression of CD8+ CD68+ M1 macrophage markers with upregulation of iNOS and co-expression of CD163+. Alternatively, Arg1+ Fizz1+ M2 macrophage markers were downregulated with increased iNOS/Arg1 ratio. TFR1, cubilin, and DMT1, as iron transport systems, were increased compared to sham but were significant after 72 h, while ZIP8 showed no significant change. There was a correlation between iron overload and M1 macrophage polarization with CD163+ phenotype, together with fibrotic changes. The intracellular iron overload with downregulation of ferritin was strongly related to macrophage polarization that was exaggerated at 72 h. Finally, early introduced therapy to target free iron during sepsis is a proposed novel solution for protecting the renal tissue from acute injury due to macrophage activation that may end up with chronic kidney injury, if not mortality.https://www.frontiersin.org/articles/10.3389/fphys.2025.1430946/fullsepsisacute kidney injurymacrophage polarizationiron homeostasismacrophage markersiron transporters |
| spellingShingle | Mira Hanna Ahmed M. A. Akabawy Mohamed Mansour Khalifa Mohamed Mansour Khalifa Marawan Abd Elbaset Reda Abdelnasser Imam Hanan Seddiek Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage Frontiers in Physiology sepsis acute kidney injury macrophage polarization iron homeostasis macrophage markers iron transporters |
| title | Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage |
| title_full | Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage |
| title_fullStr | Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage |
| title_full_unstemmed | Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage |
| title_short | Intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage |
| title_sort | intracellular iron accumulation throughout the progression of sepsis influences the phenotype and function of activated macrophages in renal tissue damage |
| topic | sepsis acute kidney injury macrophage polarization iron homeostasis macrophage markers iron transporters |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2025.1430946/full |
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