Aerobic exercise alleviates allergic airway inflammation by suppressing circMETTL9-mediated formation of macrophage extracellular traps

Emerging evidence suggests that aerobic exercise exerts beneficial effects on asthma. Previous studies have demonstrated that cell communication can drive the formation of macrophage extracellular traps (METs). However, the potential of aerobic exercise to mediate communication between airway epithelial cells and macrophages, thereby influencing MET formation, remains unexplored. Our data reveal that the upregulation of circular RNA METTL9 (circMETTL9), derived from methyltransferase-like protein 9 (METTL9) in airway epithelial cells, promotes the formation of METs. Notably, aerobic exercise was found to downregulate the expression of circMETTL9, thereby facilitating communication between airway epithelial cells and macrophages and inhibiting METs formation. Mechanistically, circMETTL9 and insulin-like growth factor binding protein 3 (IGFBP3) compete for binding to the DEXDc domain of eukaryotic translation initiation factor 4A3 (EIF4A3), which regulates METs via the C-X-C motif chemokine ligand 12(CXCL12) -C-X-C Chemokine Receptor type 4(CXCR4) signaling axis. This study provides robust molecular evidence supporting aerobic exercise as a foundational pulmonary rehabilitation strategy for lung protection in asthma. Targeting circMETTL9, mimicking this exercise-mediated pathway, represents a promising therapeutic approach. These insights offer a direct mechanistic rationale for refining exercise-based rehabilitation protocols and developing novel targeted therapies.