Targeting IL-33 in COPD: mechanistic lessons from clinical trials and the path forward

BACKGROUND: Interleukin-33 (IL-33) is a promising therapeutic target in chronic obstructive pulmonary disease (COPD). However, recent clinical trial setbacks have highlighted the complexity of its biology. This review examines the functions of IL-33 in inflammation, host defense, and tissue remodeling and discusses the potential benefits and harms of targeting this pathway in patients with COPD. METHODS: We synthesize data from clinical trials of anti-IL-33/ST2 agents and integrate these findings with recent molecular and cellular immunology research to elucidate IL-33's dual functionality, induced by the reduced IL-33 and oxidized IL-33 isoforms. Additionally, we highlight the impact of modifying factors, including multimorbidity, exogenous exposures, and microbial pathogens, on the IL-33 cascade. RESULTS: Divergent trial outcomes in patients with COPD treated with anti-IL-33 and anti-ST2 antibodies revealed critical mechanistic insights. Inconsistent efficacy of single-pathway inhibitors likely reflect incomplete targeting of IL-33's dual functionality. While the IL-33red/ST2 pathway drives type 2 inflammation, it is also essential for neutrophil-mediated antibacterial host defense. In contrast, IL-33ox signals through the RAGE/EGFR axis to promote steroid-resistant epithelial remodelling and mucus hypersecretion, a pathway not addressed by ST2-targeted therapies. Experimental data suggesting a potential increase in infection risk associated with anti-IL-33 therapies further underscore the clinical relevance of these mechanistic considerations. CONCLUSIONS: Effective IL-33-targeted therapy in COPD will require a mechanistically comprehensive strategy with precision medicine approaches that address patient heterogeneity, including infection risk and comorbidity burden, and incorporate assessment of IL-33 redox states, soluble ST2, and soluble RAGE.