Pérez Diego, MarioAngelina Querencias, AlbaPat, YağızMaldonado, AngelSevilla Ortega, CarmenMartín De La Cruz, LeticiaYazici, DuyguRückert, BeateSokolowska, MilenaMartín-Fontecha Corrales, María Del MarAkdis , MübeccelAkdis, Cezmi APalomares Gracia, Óscar2025-07-152025-07-152025-05Pérez-Diego M, Angelina A, Pat Y, Maldonado A, Sevilla-Ortega C, Martín-Cruz L, Yazici D, Rückert B, Sokolowska M, Martín-Fontecha M, Akdis M, Akdis CA, Palomares O. Cannabinoid WIN55,212-2 restores bronchial epithelium by regulating oxidative stress and STAT6 phosphorylation. J Allergy Clin Immunol. 2025 May 16:S0091-6749(25)00551-2. doi: 10.1016/j.jaci.2025.05.002. Epub ahead of print. PMID: 40383489.10.1016/j.jaci.2025.05.002https://hdl.handle.net/20.500.14352/122508Background: Viral infections and type 2 immune responses perpetuate airway epithelial barrier dysfunction and inflammation, leading to the development and progression of asthma. The synthetic cannabinoid WIN55,212-2 displays anti-inflammatory properties by acting on different immune system cells. Objective: We sought to investigate the capacity of WIN55,212-2 to restore bronchial epithelial barrier function in asthma in the context of viral infections or type 2-driven inflammation. Methods: Air-liquid interface cultures of human bronchial epithelial cells and human bronchial epithelial spheroids were generated to assess the capacity of WIN55,212-2 to restore airway epithelial barrier damage induced by human rhinovirus A16 (RV-A16) infection or type 2 inflammation. RT-PCR, cytokine quantification, permeability assays, metabolic studies, flow cytometry, and Western blot techniques were employed to assess the effects of WIN55,212-2 on the airway epithelium. The in vivo relevance of our findings was evaluated in a murine model of IL-13-induced airway inflammation. Results: Prophylactic and therapeutic administration of WIN55,212-2 accelerated the recovery from RV-A16-induced bronchial epithelial barrier damage. WIN55,212-2 inhibited the acquisition of IL-13-induced type 2 asthma features in air-liquid interface cultures, self-assembled bronchial epithelial spheroids, and in vivo asthma model of airway inflammation and epithelial dysfunction. Mechanistically, WIN55,212-2 impaired IL-13-induced oxidative stress in epithelial cells, restoring the activity of protein tyrosine phosphatases, which in turn inhibited pSTAT6-mediated signaling pathways and asthma features. Conclusions: The cannabinoid WIN55,212-2 displays airway epithelial barrier protective effects during RV-A16 infection or type 2 inflammation by mechanisms associated with the modulation of oxidative metabolism and pSTAT6-mediated signaling.engjournal articlehttps://doi.org/10.1016/j.jaci.2025.05.002restricted access577.334CannabinoidsWIN55,212-2Airway epithelial cellsAsthmaMetabolic reprogrammingOxidative stressType 2 cytokine signalingType 2 inflammationViral infectionsBioquímica (Química)2302 Bioquímica