m6A-mediated HDAC9 upregulation promotes particulate matter-induced airway inflammation via epigenetic control of DUSP9-MAPK axis and acts as an inhaled nanotherapeutic target

被引：2

作者：

Zeng, Yingying ^{[1
,2
]}

Bai, Xin ^{[3
]}

Zhu, Guiping ^{[1
,2
]}

Zhu, Mengchan ^{[1
]}

Peng, Wenjun ^{[1
,2
]}

Song, Juan ^{[1
]}

Cai, Hui ^{[1
]}

Ye, Ling ^{[2
]}

Chen, Cuicui ^{[1
]}

Song, Yuanlin ^{[1
,4
,5
,6
]}

Jin, Meiling ^{[2
]}

Zhang, Xue-Qing ^{[3
]}

Wang, Jian ^{[1
]}

机构：

[1] Fudan Univ, Zhongshan Hosp, Dept Pulm Med, Shanghai 200032, Peoples R China

[2] Fudan Univ, Zhongshan Hosp, Dept Allergy, Shanghai 200032, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China

[4] Fudan Univ, Zhongshan Hosp, Dept Pulm Med, Shanghai Key Lab Lung Inflammat & Injury, Shanghai 200032, Peoples R China

[5] Shanghai Inst Infect Dis & Biosecur, Shanghai 200032, Peoples R China

[6] Shanghai Resp Res Inst, Shanghai 200032, Peoples R China

来源：

JOURNAL OF HAZARDOUS MATERIALS | 2024年 / 477卷

基金：

中国国家自然科学基金;

关键词：

Particulate matter; Histone deacetylase 9; Airway inflammation; Epigenetic regulation; Inhaled lipid nanoparticle; HISTONE DEACETYLASES; POLLUTION; EXPRESSION; ERK;

D O I：

10.1016/j.jhazmat.2024.135093

中图分类号：

X [环境科学、安全科学];

学科分类号：

08 ; 0830 ;

摘要：

Exposure to particulate matter (PM) can cause airway inflammation and worsen various airway diseases. However, the underlying molecular mechanism by which PM triggers airway inflammation has not been completely elucidated, and effective interventions are lacking. Our study revealed that PM exposure increased the expression of histone deacetylase 9 (HDAC9) in human bronchial epithelial cells and mouse airway epithelium through the METTL3/m6A 6 A methylation/IGF2BP3 pathway. Functional assays showed that HDAC9 upregulation promoted PM-induced airway inflammation and activation of MAPK signaling pathway in vitro and in vivo. . Mechanistically, HDAC9 modulated the deacetylation of histone 4 acetylation at K12 (H4K12) in the promoter region of dual specificity phosphatase 9 (DUSP9) to repress the expression of DUSP9 and resulting in the activation of MAPK signaling pathway, thereby promoting PM-induced airway inflammation. Additionally, HDAC9 bound to MEF2A to weaken its anti-inflammatory effect on PM-induced airway inflammation. Then, we developed a novel inhaled lipid nanoparticle system for delivering HDAC9 siRNA to the airway, offering an effective treatment for PM-induced airway inflammation. Collectively, we elucidated the crucial regulatory mechanism of HDAC9 in PM-induced airway inflammation and introduced an inhaled therapeutic approach targeting HDAC9. These findings contribute to alleviating the burden of various airway diseases caused by PM exposure.

引用

页数：18