Loss of MBD2 ameliorates LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis.

Abstract

Apoptosis of alveolar epithelial cells is a critical initial link in the pathogenesis of acute lung injury (ALI), recent studies have revealed that Methyl-CpG binding domain protein 2 (MBD2) was involved in the execution of apoptosis, yet its role in ALI remained unclear. In the present study, we aim to explore the role and mechanism of MBD2 in the pathogenesis of ALI. We have found that MBD2 expression, in parallel to apoptosis, increased in alveolar epithelial cells of mice treated with LPS, knockout of MBD2 reduced apoptosis and protected mice from LPS-induced ALI. In MLE-12 cells, a cell line of murine alveolar epithelial cells, LPS induced MBD2 expression and apoptosis in a dose- and time-dependent manner. Knockdown of MBD2 with shRNA alleviated, while overexpression of MBD2 increased LPS-induced apoptosis. Mechanistically, intracellular zinc level decreased when MLE-12 cells were treated with LPS. MBD2 knockdown restored intracellular zinc level after LPS treatment, and MBD2 overexpression further aggravated LPS-induced intracellular zinc loss. Metal transcription factor 1 (MTF1) is a critical transcription factor in charge of intracellular zinc efflux. LPS treatment induced MTF1 expression both in vivo and in vitro. Inhibition of MTF1 reduced LPS-induced apoptosis in MLE-12 cells. MBD2 could bind to the promoter region of MTF1 and promote MTF1 expression. Collectively, these data indicated that loss of MBD2-ameliorated LPS-induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis by upregulating MTF1.

• Authors: Jiqiang Liu, Shuo Yao, Jingsi Jia, Zhifeng Chen, Yu Yuan, Yi He, Binaya Wasti, Wentao Duan, Danhong Li, Guyi Wang, Aijun Jia, Wenjin Sun, Shuangfa Qiu, Libing Ma, Jianmin Li, Yi Liu, Jianfei Zheng, Xudong Xiang, Xiufeng Zhang, Shaokun Liu, Zhibiao He, Zhenyu Peng, Hongliang Zhang, Dongshan Zhang, Bing Xiao
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 36 Issue 2 Pg. e22162 (02 2022) ISSN: 1530-6860 [Electronic] United States
• PMID: 35061304 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Federation of American Societies for Experimental Biology.

Chemical References

• DNA-Binding Proteins
• Lipopolysaccharides
• Mbd2 protein, mouse
• RNA, Small Interfering
• Transcription Factors
• Zinc

Topics

• Acute Lung Injury (genetics)
• Alveolar Epithelial Cells (drug effects, metabolism)
• Animals
• Apoptosis (drug effects, genetics)
• Cell Line
• DNA-Binding Proteins (genetics)
• Gene Expression Regulation (drug effects, genetics)
• Homeostasis (drug effects, genetics)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Promoter Regions, Genetic (drug effects, genetics)
• RNA, Small Interfering (genetics)
• Transcription Factors (metabolism)
• Up-Regulation (drug effects, genetics)
• Zinc (metabolism)