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

Abstract

<b>Rationale:</b> IL-33 is a proinflammatory cytokine thought to play a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). A recent clinical trial using an anti-IL-33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD. <b>Objectives:</b> This study aimed to understand the effects of smoking status on IL-33. <b>Methods:</b> We investigated the association of smoking status with the level of gene expression of <i>IL-33</i> in the airways in eight independent transcriptomic studies of lung airways. Additionally, we performed Western blot analysis and immunohistochemistry for IL-33 in lung tissue to assess protein levels. <b>Measurements and Main Results:</b> Across the bulk RNA-sequencing datasets, <i>IL-33</i> gene expression and its signaling pathway were significantly lower in current versus former or never-smokers and increased upon smoking cessation (<i>P</i> < 0.05). Single-cell sequencing showed that <i>IL-33</i> is predominantly expressed in resting basal epithelial cells and decreases during the differentiation process triggered by smoke exposure. We also found a higher transitioning of this cellular subpopulation into a more differentiated cell type during chronic smoking, potentially driving the reduction of <i>IL-33</i>. Protein analysis demonstrated lower IL-33 levels in lung tissue from current versus former smokers with COPD and a lower proportion of IL-33-positive basal cells in current versus ex-smoking controls. <b>Conclusions:</b> We provide strong evidence that cigarette smoke leads to an overall reduction in IL-33 expression in transcriptomic and protein level, and this may be due to the decrease in resting basal cells. Together, these findings may explain the clinical observation that a recent antibody-based anti-IL-33 treatment is more effective in former than current smokers with COPD.