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METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury

Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies...

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Autores principales: Zhang, Hao, Wu, Dan, Wang, Yanghanzhao, Guo, Kefang, Spencer, Charles B., Ortoga, Lilibeth, Qu, Mengdi, Shi, Yuxin, Shao, Yuwen, Wang, Zhiping, Cata, Juan P., Miao, Changhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10504453/
https://www.ncbi.nlm.nih.gov/pubmed/37715457
http://dx.doi.org/10.1002/ctm2.1389
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author Zhang, Hao
Wu, Dan
Wang, Yanghanzhao
Guo, Kefang
Spencer, Charles B.
Ortoga, Lilibeth
Qu, Mengdi
Shi, Yuxin
Shao, Yuwen
Wang, Zhiping
Cata, Juan P.
Miao, Changhong
author_facet Zhang, Hao
Wu, Dan
Wang, Yanghanzhao
Guo, Kefang
Spencer, Charles B.
Ortoga, Lilibeth
Qu, Mengdi
Shi, Yuxin
Shao, Yuwen
Wang, Zhiping
Cata, Juan P.
Miao, Changhong
author_sort Zhang, Hao
collection PubMed
description Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis‐induced acute lung injury (SI‐ALI). We demonstrate that NETs induce SI‐ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI‐ALI is accompanied by upregulation of ferroptosis depending on METTL3‐induced m6A modification of hypoxia‐inducible factor‐1α (HIF‐1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI‐ALI caused by NETs in a caecum ligation and puncture (CLP)‐induced SI‐ALI model using METTL3 condition knockout (CKO) mice and wild‐type mice. Our results indicate the crucial role of NETs in the progression of SI‐ALI via NET‐activated METTL3 m6A‐IGF2BP2‐dependent m6A modification of HIF‐1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells.
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spelling pubmed-105044532023-09-17 METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury Zhang, Hao Wu, Dan Wang, Yanghanzhao Guo, Kefang Spencer, Charles B. Ortoga, Lilibeth Qu, Mengdi Shi, Yuxin Shao, Yuwen Wang, Zhiping Cata, Juan P. Miao, Changhong Clin Transl Med Research Articles Neutrophil extracellular traps (NETs), released by polymorphonuclear neutrophils (PMNs), exert a robust antimicrobial function in infectious diseases such as sepsis. NETs also contribute to the pathogenesis and exacerbation of sepsis. Although the lung is highly vulnerable to infections, few studies have explored the role of NETs in sepsis‐induced acute lung injury (SI‐ALI). We demonstrate that NETs induce SI‐ALI via enhanced ferroptosis in alveolar epithelial cells. Our findings reveal that the excessive release of NETs in patients and mice with SI‐ALI is accompanied by upregulation of ferroptosis depending on METTL3‐induced m6A modification of hypoxia‐inducible factor‐1α (HIF‐1α) and subsequent mitochondrial metabolic reprogramming. In addition to conducting METTL3 overexpression and knockdown experiments in vitro, we also investigated the impact of ferroptosis on SI‐ALI caused by NETs in a caecum ligation and puncture (CLP)‐induced SI‐ALI model using METTL3 condition knockout (CKO) mice and wild‐type mice. Our results indicate the crucial role of NETs in the progression of SI‐ALI via NET‐activated METTL3 m6A‐IGF2BP2‐dependent m6A modification of HIF‐1α, which further contributes to metabolic reprogramming and ferroptosis in alveolar epithelial cells. John Wiley and Sons Inc. 2023-09-15 /pmc/articles/PMC10504453/ /pubmed/37715457 http://dx.doi.org/10.1002/ctm2.1389 Text en © 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Zhang, Hao
Wu, Dan
Wang, Yanghanzhao
Guo, Kefang
Spencer, Charles B.
Ortoga, Lilibeth
Qu, Mengdi
Shi, Yuxin
Shao, Yuwen
Wang, Zhiping
Cata, Juan P.
Miao, Changhong
METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
title METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
title_full METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
title_fullStr METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
title_full_unstemmed METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
title_short METTL3‐mediated N6‐methyladenosine exacerbates ferroptosis via m6A‐IGF2BP2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
title_sort mettl3‐mediated n6‐methyladenosine exacerbates ferroptosis via m6a‐igf2bp2‐dependent mitochondrial metabolic reprogramming in sepsis‐induced acute lung injury
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10504453/
https://www.ncbi.nlm.nih.gov/pubmed/37715457
http://dx.doi.org/10.1002/ctm2.1389
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