Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex

Extract The airway epithelium plays a central role in the initiation and development of chronic airway diseases [1]. It is the first line of defence against the external environment; therefore, numerous inflammatory and tissue remodelling pathways exist to protect against damage caused by constant exposure to inhaled stimuli (e.g. allergens, cigarette smoke or pathogens) [1, 2]. Dysregulation of these pathways alters the structure of the airway epithelium, making it an inadequate defence against further insult from inhaled stimuli. This results in a cycle of abnormal epithelial responses and further damage, which may contribute to irreversible airway changes and severe chronic airway disease, such as chronic obstructive pulmonary disease (COPD) [1, 2]. Graphical abstract IL-33ox binds to receptor for advanced glycation end products (RAGE) to signal via epidermal growth factor receptor (EGFR). Activation of the IL-33ox–RAGE/EGFR pathway redirects epithelial cell fate, promoting a mucin hypersecretion phenotype at the expense of epithelial defence functions. Background Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. Methods In vitro epithelial damage assays and three-dimensional, air–liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. Results We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. Conclusions Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD. Tweetable abstract An ST2-independent signalling complex of oxidised IL-33, receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) governs epithelial remodelling and mucin hypersecretion in COPD https://bit.ly/3pxgaqx