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Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy

Encephalopathy is a frequent and lethal consequence of sepsis. Recently, a growing body of evidence has provided important insights into the role of iron dyshomeostasis in the context of inflammation. The molecular mechanisms underlying iron dyshomeostasis and its relationship with macrophage phenot...

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Autores principales: Sharawy, Nivin, Imam, Ahmad Abdel-Aliem, Aboulhoda, Basma Emad, Khalifa, Mohamed Mansour, Morcos, George N. B., Abd Algaleel, Waleed Ahmed, Moustafa, Passant E., Abdelbaset, Marwan A., Shoukry, Tarek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413069/
https://www.ncbi.nlm.nih.gov/pubmed/36035473
http://dx.doi.org/10.3389/fphys.2022.953206
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author Sharawy, Nivin
Imam, Ahmad Abdel-Aliem
Aboulhoda, Basma Emad
Khalifa, Mohamed Mansour
Morcos, George N. B.
Abd Algaleel, Waleed Ahmed
Moustafa, Passant E.
Abdelbaset, Marwan A.
Shoukry, Tarek
author_facet Sharawy, Nivin
Imam, Ahmad Abdel-Aliem
Aboulhoda, Basma Emad
Khalifa, Mohamed Mansour
Morcos, George N. B.
Abd Algaleel, Waleed Ahmed
Moustafa, Passant E.
Abdelbaset, Marwan A.
Shoukry, Tarek
author_sort Sharawy, Nivin
collection PubMed
description Encephalopathy is a frequent and lethal consequence of sepsis. Recently, a growing body of evidence has provided important insights into the role of iron dyshomeostasis in the context of inflammation. The molecular mechanisms underlying iron dyshomeostasis and its relationship with macrophage phenotypes are largely unknown. Here, we aimed to characterize the changes in iron-transporter and storage proteins and the microglia phenotype that occur during the course of sepsis, as well as their relationship with sepsis-induced encephalopathy. We used a cecal ligation and puncture (CLP) murine model that closely resembles sepsis-induced encephalopathy. Rats were subjected to CLP or sham laparotomy, then were neurologically assessed at 6 h, 24 h, and 3 days after sepsis induction. The serum and brain were collected for subsequent biochemical, histological, and immunohistochemical assessment. Here, an iron excess was observed at time points that followed the pro-inflammatory macrophage polarization in CLP-induced encephalopathy. Our results revealed that the upregulation of non-transferrin-bound iron uptake (NTBI) and ferritin reduction appeared to be partially responsible for the excess free iron detected within the brain tissues. We further demonstrated that the microglia were shifted toward the pro-inflammatory phenotype, leading to persistent neuro-inflammation and neuronal damage after CLP. Taken together, these findings led us to conclude that sepsis increased the susceptibility of the brain to the iron burden via the upregulation of NTBI and the reduction of ferritin, which was concomitantly and correlatively associated with dominance of pro-inflammatory microglia and could explain the neurological dysfunction observed during sepsis.
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spelling pubmed-94130692022-08-27 Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy Sharawy, Nivin Imam, Ahmad Abdel-Aliem Aboulhoda, Basma Emad Khalifa, Mohamed Mansour Morcos, George N. B. Abd Algaleel, Waleed Ahmed Moustafa, Passant E. Abdelbaset, Marwan A. Shoukry, Tarek Front Physiol Physiology Encephalopathy is a frequent and lethal consequence of sepsis. Recently, a growing body of evidence has provided important insights into the role of iron dyshomeostasis in the context of inflammation. The molecular mechanisms underlying iron dyshomeostasis and its relationship with macrophage phenotypes are largely unknown. Here, we aimed to characterize the changes in iron-transporter and storage proteins and the microglia phenotype that occur during the course of sepsis, as well as their relationship with sepsis-induced encephalopathy. We used a cecal ligation and puncture (CLP) murine model that closely resembles sepsis-induced encephalopathy. Rats were subjected to CLP or sham laparotomy, then were neurologically assessed at 6 h, 24 h, and 3 days after sepsis induction. The serum and brain were collected for subsequent biochemical, histological, and immunohistochemical assessment. Here, an iron excess was observed at time points that followed the pro-inflammatory macrophage polarization in CLP-induced encephalopathy. Our results revealed that the upregulation of non-transferrin-bound iron uptake (NTBI) and ferritin reduction appeared to be partially responsible for the excess free iron detected within the brain tissues. We further demonstrated that the microglia were shifted toward the pro-inflammatory phenotype, leading to persistent neuro-inflammation and neuronal damage after CLP. Taken together, these findings led us to conclude that sepsis increased the susceptibility of the brain to the iron burden via the upregulation of NTBI and the reduction of ferritin, which was concomitantly and correlatively associated with dominance of pro-inflammatory microglia and could explain the neurological dysfunction observed during sepsis. Frontiers Media S.A. 2022-08-12 /pmc/articles/PMC9413069/ /pubmed/36035473 http://dx.doi.org/10.3389/fphys.2022.953206 Text en Copyright © 2022 Sharawy, Imam, Aboulhoda, Khalifa, Morcos, Abd Algaleel, Moustafa, Abdelbaset and Shoukry. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Sharawy, Nivin
Imam, Ahmad Abdel-Aliem
Aboulhoda, Basma Emad
Khalifa, Mohamed Mansour
Morcos, George N. B.
Abd Algaleel, Waleed Ahmed
Moustafa, Passant E.
Abdelbaset, Marwan A.
Shoukry, Tarek
Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
title Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
title_full Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
title_fullStr Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
title_full_unstemmed Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
title_short Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
title_sort iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413069/
https://www.ncbi.nlm.nih.gov/pubmed/36035473
http://dx.doi.org/10.3389/fphys.2022.953206
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