IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels.

Area of Science:

• Respiratory Medicine
• Immunology
• Molecular Biology

Background:

• Interleukin-33 (IL-33) is a proinflammatory cytokine implicated in asthma and COPD pathogenesis.
• Clinical trials show anti-IL-33 therapy benefits ex-smokers but not current smokers with COPD, suggesting smoking status impacts IL-33 efficacy.

Purpose of the Study:

• To investigate the influence of smoking status on IL-33 levels in the airways.
• To understand the molecular mechanisms behind observed differences in IL-33 response to therapy.

Main Methods:

• Analysis of eight transcriptomic studies to assess IL-33 gene expression in relation to smoking status.
• Western blot and immunohistochemistry to evaluate IL-33 protein levels in lung tissue.
• Single-cell sequencing to identify specific cell types expressing IL-33 and their response to smoke exposure.

Main Results:

• Current smokers exhibited significantly lower IL-33 gene expression and pathway activity compared to former or never-smokers.
• IL-33 expression decreased with smoke-induced epithelial cell differentiation, particularly in resting basal cells.
• Protein analysis confirmed lower IL-33 levels and fewer IL-33-positive basal cells in current smokers with COPD.

Conclusions:

• Cigarette smoke significantly reduces IL-33 expression at both transcriptomic and protein levels.
• This reduction is likely due to a decrease in resting basal epithelial cells affected by chronic smoking.
• Findings support the differential efficacy of anti-IL-33 treatments based on smoking status in COPD patients.