• Alen Faiz, Rashad M Mahbub, Fia Sabrina Boedijono, Milan I Tomassen, Wierd Kooistra, Wim Timens, Martijn 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 F Chung, Anne van der Does, Pieter S Hiemstra, Helene Goulaouic, Heming Xing, Raolat Abdulai, Emanuele de Rinaldis, Danen Cunoosamy, Sivan Harel, David Lederer, Michael C Nivens, Peter A Wark, KerstjensHuib A MHAMGroningen Research Institute for Asthma and COPD.Department of Pulmonary Diseases, and., Machteld N Hylkema, Corry-Anke Brandsma, and Maarten van den Berge.
• Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.
• Am. J. Respir. Crit. Care Med. 2023 Nov 15; 208 (10): 107510871075-1087.

AbstractRationale: 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.

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