Oxidised IL-33 signals via RAGE/EGFR to drive a COPD-associated phenotype

Background: Remodelling of the airway epithelium is a key feature of chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 is a multifunctional cytokine that drives COPD pathology. Upon tissue damage epithelial cells release IL-33, which binds its receptor ST2 on immune cells leading to airway inflammation. Oxidation of IL-33 via disulphide bond formation, results in conformational changes that disrupt ST2 binding. Objective: To identify whether oxidised IL-33 (IL-33ox) has functional activities that are independent of ST2 in the airway epithelium. Methods: We used in vitro epithelial damage assays and 3D cell culture models of healthy and COPD epithelia to elucidate the role of IL-33ox. Tozorakimab (MEDI3506), a high-affinity human IgG1 monoclonal antibody, was used to inhibit IL-33 signalling. Results: IL-33ox activates an alternative, ST2-independent pathway through a signalling complex of receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on the airway epithelium. Activation of the IL-33ox–RAGE/EGFR pathway in healthy airway epithelial cells impaired epithelial wound closure and led to mucus hypersecretion, mimicking the phenotype of COPD-derived cells. In COPD epithelia, inhibition of IL-33ox signalling reduced mucus synthesis and secretion thereby reversing key pathogenic features of COPD. Gene set enrichment analysis showed that gene signatures defining the effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. Conclusion: Our data reveal a previously unknown IL-33ox–RAGE/EGFR epithelial signalling pathway, which governs key features of COPD and could be an attractive therapeutic target.