Pérez-Diego Mario, Angelina Alba, Pat Yağız, Maldonado Angel, Sevilla-Ortega Carmen, Martín-Cruz Leticia, Yazici Duygu, Rückert Beate, Sokolowska Milena, Martín-Fontecha Mar, Akdis Mübeccel, Akdis Cezmi A, Palomares Oscar
Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University of Madrid, Madrid, Spain.
Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.
J Allergy Clin Immunol. 2025 Sep;156(3):651-667. doi: 10.1016/j.jaci.2025.05.002. Epub 2025 May 16.
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.
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.
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.
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.
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.
