Oxidative stress-mediated activation of FTO exacerbates impairment of the epithelial barrier by up-regulating<i> IKBKB</i> via N6-methyladenosine-dependent mRNA stability in asthmatic mice exposed to PM2.5

作者全名："Xiong, Anying; He, Xiang; Liu, Shengbin; Ran, Qin; Zhang, Lei; Wang, Junyi; Jiang, Manling; Niu, Bin; Xiong, Ying; Li, Guoping"

作者地址："[Xiong, Anying; He, Xiang; Liu, Shengbin; Ran, Qin; Zhang, Lei; Wang, Junyi; Jiang, Manling; Xiong, Ying; Li, Guoping] Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Inst Resp Hlth, Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610031, Peoples R China; [Xiong, Anying; He, Xiang; Liu, Shengbin; Ran, Qin; Zhang, Lei; Wang, Junyi; Jiang, Manling; Niu, Bin; Li, Guoping] ChongQing Med Univ, Chengdu Peoples Hosp Branch 3, Dept Pulm & Crit Care Med, Affiliated Hosp,Natl Clin Res Ctr Resp Dis, Chengdu 610031, Peoples R China; [He, Xiang] Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Natl Ctr Resp Med, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis,, Guangzhou 510120, Guangdong, Peoples R China; [Xiong, Ying] Sichuan friendship Hosp, Dept Pulm & Crit Care Med, Chengdu 610000, Peoples R China; [Zhang, Lei; Jiang, Manling] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China"

通信作者："He, X; Xiong, Y; Li, GP (通讯作者)，Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Inst Resp Hlth, Lab Allergy & Precis Med,Affiliated Hosp, Chengdu 610031, Peoples R China.; He, X; Li, GP (通讯作者)，ChongQing Med Univ, Chengdu Peoples Hosp Branch 3, Dept Pulm & Crit Care Med, Affiliated Hosp,Natl Clin Res Ctr Resp Dis, Chengdu 610031, Peoples R China."

来源：ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY

ESI学科分类：ENVIRONMENT/ECOLOGY

WOS号：WOS:001181777400001

JCR分区：Q1

影响因子：6.2

年份：2024

卷号：272

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：PM2.5; Asthma; Oxidative stress; FTO; M6A; IKBKB; Epithelial barrier

摘要："In order to comprehend the underlying mechanisms contributing to the development and exacerbation of asthma resulting from exposure to fine particulate matter (PM2.5), we established an asthmatic model in fat mass and obesity-associated gene knockdown mice subjected to PM2.5 exposure. Histological analyses using hematoxylineosin (HE) and Periodic Acid-Schiff (PAS) staining revealed that the down-regulation of the fat mass and obesityassociated gene (Fto) expression significantly ameliorated the pathophysiological alterations observed in asthmatic mice exposed to PM2.5. Furthermore, the down-regulation of Fto gene expression effectively attenuated damage to the airway epithelial barrier. Additionally, employing in vivo and in vitro models, we elucidated that PM2.5 modulated FTO expression by inducing oxidative stress. Asthmatic mice exposed to PM2.5 exhibited elevated Fto expression, which correlated with increased levels of reactive oxygen species. Similarly, when cells were exposed to PM2.5, FTO expression was up-regulated in a ROS-dependent manner. Notably, the administration of N-acetyl cysteine successfully reversed the PM2.5-induced elevation in FTO expression. Concurrently, we performed transcriptome-wide Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) analysis subsequent to PM2.5 exposure. Through the implementation of Gene Set Enrichment Analysis and m6A-IP-qPCR, we successfully identified inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) as a target gene regulated by FTO. Interestingly, exposure to PM2.5 led to increased expression of IKBKB, while m6A modification on IKBKB mRNA was reduced. Furthermore, our investigation revealed that PM2.5 also regulated IKBKB through oxidative stress. Significantly, the down-regulation of IKBKB effectively mitigated epithelial barrier damage in cells exposed to PM2.5 by modulating nuclear factor-kappa B (NF-kappa B) signaling. Importantly, we discovered that decreased m6A modification on IKBKB mRNA facilitated by FTO enhanced its stability, consequently resulting in up-regulation of IKBKB expression. Collectively, our findings propose a novel role for FTO in the regulation of IKBKB through m6A-dependent mRNA stability in the context of PM2.5-induced oxidative stress. Therefore, it is conceivable that the utilization of antioxidants or inhibition of FTO could represent potential therapeutic strategies for the management of asthma exacerbated by PM2.5 exposure."

基金机构："National Natural Science Foundation of China [81970026, 82370023, 82370022]; China Postdoctoral Science Foundation [2023M730799]; Chengdu High-level Key Clinical Specialty Construction Project [ZX20201202020]; Chengdu Science and Technology Bureau [2021-YF09-00102-SN]; Health Commission of Chengdu [2021040, 2022193]; Sichuan medical association [Q20009]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81970026, 82370023, 82370022) , China Postdoctoral Science Foundation (2023M730799) , Chengdu High-level Key Clinical Specialty Construction Project (ZX20201202020) , Chengdu Science and Technology Bureau (2021-YF09-00102-SN) , Health Commission of Chengdu (2021040, 2022193) , Sichuan medical association (Q20009) ."