RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis

Xiao Han; Lijuan Liu; Saihua Huang; Wenfeng Xiao; Yajing Gao; Weitao Zhou; Caiyan Zhang; Hongmei Zheng; Lan Yang; Xueru Xie; Qiuyan Liang; Zikun Tu; Hongmiao Yu; Jinrong Fu; Libo Wang; Xiaobo Zhang; Liling Qian; Yufeng Zhou

doi:10.1038/s41467-023-43219-w

Nature Communications (Nov 2023)

RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis

Xiao Han,
Lijuan Liu,
Saihua Huang,
Wenfeng Xiao,
Yajing Gao,
Weitao Zhou,
Caiyan Zhang,
Hongmei Zheng,
Lan Yang,
Xueru Xie,
Qiuyan Liang,
Zikun Tu,
Hongmiao Yu,
Jinrong Fu,
Libo Wang,
Xiaobo Zhang,
Liling Qian,
Yufeng Zhou

Affiliations

Xiao Han: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Lijuan Liu: Department of Respiratory Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Saihua Huang: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Wenfeng Xiao: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Yajing Gao: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Weitao Zhou: Department of Respiratory Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Caiyan Zhang: Department of Critical Care Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Hongmei Zheng: Department of Respiratory Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Lan Yang: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Xueru Xie: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Qiuyan Liang: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Zikun Tu: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Hongmiao Yu: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University
Jinrong Fu: Department of General Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Libo Wang: Department of Respiratory Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Xiaobo Zhang: Department of Respiratory Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Liling Qian: Department of Respiratory Medicine, Children’s Hospital of Fudan University, National Children’s Medical Center
Yufeng Zhou: Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University

DOI: https://doi.org/10.1038/s41467-023-43219-w
Journal volume & issue: Vol. 14, no. 1
pp. 1 – 20

Abstract

Read online

Abstract N 6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

About the journal