IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels
Alen Faiz, Rashad Mohammad Mahbub, Fia Boedijono, Milan I. Tomassen, Wierd Kooistra, Wim Timens, Martijn C. Nawijn, Philip M. Hansbro, Matt D. Johansen, Simon D. Pouwels, Irene H. Heijink, Florian Massip, Maria Stella de Biase, Roland F. Schwarz, Ian M. Adcock, Kian Fan Chung, Anne M. van der Does, Pieter S. Hiemstra, Hélène Goulaouic, Heming Xing, Raolat M. Abdulai, Emanuele de Rinaldis, Danen Cunoosamy, Sivan Harel, David J. Lederer, Michael C. Nivens, Peter Wark, Huib A.M. Kerstjens, Machteld N. Hylkema, Corry‐Anke Brandsma, Maarten van den Berge
Abstract
Abstract Rationale 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. Objectives This study aimed to understand the effects of smoking status on IL-33. Methods We investigated the association of smoking status with the level of gene expression of IL-33 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. Measurements and Main Results Across the bulk RNA-sequencing datasets, IL-33 gene expression and its signaling pathway were significantly lower in current versus former or never-smokers and increased upon smoking cessation (P < 0.05). Single-cell sequencing showed that IL-33 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 IL-33. 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. Conclusions 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.