Cannabinoid WIN55,212-2 restores bronchial epithelium by regulating oxidative stress and STAT6 phosphorylation

Pérez-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. J Allergy Clin Immunol. 2025 May 16:S0091-6749(25)00551-2. doi: 10.1016/j.jaci.2025.05.002.

Abstract

Background

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.

Objectives

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 (ALI) 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 ALI 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 inhibits 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 to the modulation of oxidative metabolism and pSTAT6-mediated signaling.

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