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 () and Yufeng Zhou ()
Additional contact information
Xiao Han: Fudan University
Lijuan Liu: National Children’s Medical Center
Saihua Huang: Fudan University
Wenfeng Xiao: Fudan University
Yajing Gao: Fudan University
Weitao Zhou: National Children’s Medical Center
Caiyan Zhang: National Children’s Medical Center
Hongmei Zheng: National Children’s Medical Center
Lan Yang: Fudan University
Xueru Xie: Fudan University
Qiuyan Liang: Fudan University
Zikun Tu: Fudan University
Hongmiao Yu: Fudan University
Jinrong Fu: National Children’s Medical Center
Libo Wang: National Children’s Medical Center
Xiaobo Zhang: National Children’s Medical Center
Liling Qian: National Children’s Medical Center
Yufeng Zhou: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract N6-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.

Date: 2023
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DOI: 10.1038/s41467-023-43219-w

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