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

N-6-methyladenosine (m(6)A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m(6)A 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, m(6)A-sequencing shows that loss of METTL3 impairs the m(6)A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m(6)A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m(6)A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.