IL-33 Expression Is Lower in Current Smokers at Both Transcriptomic and Protein Level

Cambridge Lung Cancer Early Detection Programme, 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 GoulaouicHeming Xing, Raolat Abdulai, Emanuele de Rinaldis, Danen Cunoosamy, Sivan Harel, David Lederer, Michael C Nivens, Peter A Wark, Huib A M Kerstjens, Machteld N Hylkema, Corry-Anke Brandsma, Maarten van den Berge

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

INTRODUCTION: IL-33 is a pro-inflammatory cytokine thought to play a role in the pathogenesis of asthma and COPD. A recent clinical trial using the anti-IL33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD. In this study, we 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 IL33 in the airways in eight independent transcriptomic studies of lung airways. Additionally, we performed western blot and immunohistochemistry for IL-33 in lung tissue to assess protein levels.

RESULTS: Across the bulk RNA-sequencing datasets, IL-33 gene expression and its signaling pathway were significantly lower in current- compared to ex- 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 sub-population 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 COPD current- compared to ex-smokers and a lower proportion of IL-33 positive basal cells in current versus ex-smoking controls.

CONCLUSION: We provide strong evidence that cigarette smoke leads to an overall reduction in IL33 expression in both 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 ex- than current smokers with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Original languageEnglish
Pages (from-to)1075-1087
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume208
Issue number10
Early online date14-Sept-2023
DOIs
Publication statusPublished - 15-Nov-2023

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