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RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
Xiao Han1,2, Lijuan Liu3, Saihua Huang4,5
1Institute 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, Shanghai, 200032, China. sqhx12@126.com.
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.
Insights
The study reveals that low levels of METTL3, an enzyme crucial for N6-methyladenosine (m6A) modification, worsen allergic asthma by promoting M2 macrophage activation. This finding offers new therapeutic targets for allergic airway inflammation.
Area of Science:
- Immunology
- Epigenetics
- Molecular Biology
Background:
- N6-methyladenosine (m6A) is a prevalent mRNA modification impacting biological processes.
- The role of m6A in allergic asthma and macrophage homeostasis is not well understood.
Purpose of the Study:
- To investigate the function of m6A methyltransferases METTL3 in allergic asthma.
- To elucidate the mechanisms by which METTL3 regulates macrophage homeostasis and allergic airway inflammation.
Main Methods:
- Analysis of METTL3 expression in macrophages from asthma patients.
- Conditional knockout of Mettl3 in myeloid cells.
- Loss and gain functional studies involving PI3K/AKT and JAK/STAT6 signaling pathways.
- m6A-sequencing to identify target mRNAs and regulatory interactions.
Main Results:
- Reduced METTL3 expression in macrophages from childhood allergic asthma patients.
- Mettl3 deficiency in myeloid cells exacerbates allergic airway inflammation by enhancing Th2 response and M2 macrophage activation.
- METTL3 suppresses M2 macrophage activation via PI3K/AKT and JAK/STAT6 signaling.
- Loss of METTL3 leads to impaired m6A-YTHDF3-dependent degradation of PTX3 mRNA, correlating with asthma severity.
- METTL3/YTHDF3-m6A/PTX3 interactions regulate macrophage autophagy by modulating STX17 expression.
Conclusions:
- METTL3 plays a critical role in suppressing M2 macrophage activation and mitigating allergic airway inflammation.
- The METTL3/YTHDF3-m6A/PTX3 axis is a key regulator of macrophage homeostasis and allergic asthma.
- Targeting the m6A pathway, particularly METTL3, presents a potential therapeutic strategy for allergic asthma.
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