Cargando…

Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in seps...

Descripción completa

Detalles Bibliográficos
Autores principales: He, Ruyuan, Liu, Bohao, Xiong, Rui, Geng, Boxin, Meng, Heng, Lin, Weichen, Hao, Bo, Zhang, Lin, Wang, Wei, Jiang, Wenyang, Li, Ning, Geng, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810876/
https://www.ncbi.nlm.nih.gov/pubmed/35110526
http://dx.doi.org/10.1038/s41420-021-00807-3
_version_ 1784644323411755008
author He, Ruyuan
Liu, Bohao
Xiong, Rui
Geng, Boxin
Meng, Heng
Lin, Weichen
Hao, Bo
Zhang, Lin
Wang, Wei
Jiang, Wenyang
Li, Ning
Geng, Qing
author_facet He, Ruyuan
Liu, Bohao
Xiong, Rui
Geng, Boxin
Meng, Heng
Lin, Weichen
Hao, Bo
Zhang, Lin
Wang, Wei
Jiang, Wenyang
Li, Ning
Geng, Qing
author_sort He, Ruyuan
collection PubMed
description Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.
format Online
Article
Text
id pubmed-8810876
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-88108762022-02-10 Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury He, Ruyuan Liu, Bohao Xiong, Rui Geng, Boxin Meng, Heng Lin, Weichen Hao, Bo Zhang, Lin Wang, Wei Jiang, Wenyang Li, Ning Geng, Qing Cell Death Discov Article Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis. Nature Publishing Group UK 2022-02-02 /pmc/articles/PMC8810876/ /pubmed/35110526 http://dx.doi.org/10.1038/s41420-021-00807-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
He, Ruyuan
Liu, Bohao
Xiong, Rui
Geng, Boxin
Meng, Heng
Lin, Weichen
Hao, Bo
Zhang, Lin
Wang, Wei
Jiang, Wenyang
Li, Ning
Geng, Qing
Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
title Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
title_full Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
title_fullStr Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
title_full_unstemmed Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
title_short Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury
title_sort itaconate inhibits ferroptosis of macrophage via nrf2 pathways against sepsis-induced acute lung injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8810876/
https://www.ncbi.nlm.nih.gov/pubmed/35110526
http://dx.doi.org/10.1038/s41420-021-00807-3
work_keys_str_mv AT heruyuan itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT liubohao itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT xiongrui itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT gengboxin itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT mengheng itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT linweichen itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT haobo itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT zhanglin itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT wangwei itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT jiangwenyang itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT lining itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury
AT gengqing itaconateinhibitsferroptosisofmacrophagevianrf2pathwaysagainstsepsisinducedacutelunginjury