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

Abstract

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