IL-33 expression is lower in current smokers at both transcriptomic and protein levels

Faiz, A.; Mahbub, R.M.; Boedijono, F.S.; Tomassen, M.I.; Kooistra, W.; Timens, W.; Nawijn, M.; Hansbro, P.M.; Johansen, M.D.; Pouwels, S.D.; Heijink, I.H.; Massip, F.; Biase, M.S. de; Schwarz, R.F.; Adcock, I.M.; Chung, K.F.; Does, A. van der; Hiemstra, P.S.; Goulaouic, H.; Xing, H.M.; Abdulai, R.; Rinaldis, E. de; Cunoosamy, D.; Harel, S.; Lederer, D.; Nivens, M.C.; Wark, P.A.; Kerstjens, H.A.M.; Hylkema, M.N.; Brandsma, C.A.; Berge, M. van den; Cambridge Lung Canc Early

doi:doi:10.1164/rccm.202210-1881OC

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...Show moreRationale: 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 amore 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.Show less

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IL-33 expression is lower in current smokers at both transcriptomic and protein levels