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

Area of Science:

• Immunology
• Pulmonology
• Pharmacology

Background:

• Interleukin-33 (IL-33) is a key mediator in chronic obstructive pulmonary disease (COPD) pathogenesis.
• Recent clinical trials targeting IL-33 in COPD have yielded complex and sometimes contradictory results.
• Understanding IL-33's multifaceted roles is crucial for developing effective COPD therapies.

Purpose of the Study:

• To review the diverse functions of IL-33 in COPD, encompassing inflammation, host defense, and tissue remodeling.
• To analyze the implications of IL-33 targeting strategies based on clinical trial data and molecular immunology.
• To discuss the potential benefits and risks associated with modulating the IL-33 pathway in COPD patients.

Main Methods:

• Synthesis of data from clinical trials involving anti-IL-33 and anti-ST2 agents.
• Integration of findings with current molecular and cellular immunology research.
• Elucidation of IL-33's dual functionality, influenced by reduced (IL-33red) and oxidized (IL-33ox) isoforms.
• Consideration of modifying factors like multimorbidity, exposures, and pathogens.

Main Results:

• Divergent clinical trial outcomes highlight the complexity of IL-33's role in COPD.
• The IL-33red/ST2 pathway is involved in type 2 inflammation and antibacterial defense.
• The IL-33ox/RAGE/EGFR axis promotes steroid-resistant airway remodeling and mucus hypersecretion, a pathway not targeted by ST2 inhibitors.
• Potential increased infection risk with anti-IL-33 therapies necessitates careful consideration.

Conclusions:

• Effective IL-33-targeted therapy for COPD demands a comprehensive mechanistic strategy.
• Precision medicine approaches are essential to address patient heterogeneity, including infection risk and comorbidities.
• Future strategies should incorporate assessment of IL-33 redox states, soluble ST2, and soluble RAGE.