IL-5 promotes airway remodeling in asthma by mediating epithelial-mesenchymal transition via the AKT/NLRP3 pathway

Airway remodeling, a key contributor to airflow limitation, correlates with asthma severity and progression. Eosinophilic inflammation plays significant roles in driving airway remodeling.

To investigate the effects of different treatment time and doses of anti-IL-5 monoclonal antibody (mAb) on airway remodeling and to explore the molecular mechanisms related to epithelial-mesenchymal transition.

A chronic asthma model was established using ovalbumin for 8 weeks. Anti-IL-5 mAb was administered at high (60 mg/kg) or low (20 mg/kg) doses for 4 weeks (early treatment) or 1 week (late treatment) to evaluate its effects on lung function, airway hyperresponsiveness (AHR) and remodeling. Beas-2B cells were stimulated with IL-5. RNA sequencing, molecular docking and co-immunoprecipitation were performed to analyze potential signaling pathways.

Ovalbumin exposure impaired lung function and induced eosinophilic inflammation and AHR, with collagen deposition and EMT indicating airway remodeling. Early low-dose anti-IL-5 mAb treatment significantly improved both large and small airway function and AHR, while ameliorating EMT and remodeling. Late low/high-dose treatments also improved AHR, but only high-dose improved small airway function with no significant improvement in large airway function, and remodeling improvement was inferior to early low-dose. In vitro, IL-5 downregulated E-Cadherin and upregulated N-Cadherin, with increased AKT phosphorylation. AKT interacted with NLRP3 mediating IL-5-induced EMT, which was blocked by MK2206 (AKT inhibitor) and MCC950 (NLRP3 inhibitor). Early low/high-dose anti-IL-5 mAbs inhibited AKT and NLRP3 activation, but effects diminished in late treatment.

Anti-IL-5 mAb reverses airway remodeling, with early low-dose treatment showing superior to late high-dose. It also better restores large airway function and provides comparable small airway improvement to late high-dose. Mechanistically, IL-5 promotes EMT via AKT/NLRP3 signaling, which is effectively suppressed by anti-IL-5 mAb early treatment.