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.

中文翻译：

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目前吸烟者的 IL-33 表达在转录组和蛋白质水平上均较低。

理由：IL-33 是一种促炎细胞因子，被认为在哮喘和慢性阻塞性肺病 (COPD) 的发病机制中发挥作用。最近的一项使用抗 IL-33 抗体的临床试验显示，戒烟者的病情恶化有所减少，肺功能有所改善，但目前患有慢性阻塞性肺病的吸烟者却没有这种情况。目的：本研究旨在了解吸烟状况对 IL-33 的影响。方法：我们在八项独立的肺气道转录组研究中调查了吸烟状况与气道中 IL-33 基因表达水平的关联。此外，我们对肺组织中的 IL-33 进行了蛋白质印迹分析和免疫组织化学分析，以评估蛋白质水平。测量和主要结果：在大量 RNA 测序数据集中，当前吸烟者与以前吸烟者或从不吸烟者相比，IL-33 基因表达及其信号通路显着降低，并且在戒烟后增加（P < 0.05）。单细胞测序表明，IL-33 主要在静息基底上皮细胞中表达，并在烟雾暴露引发的分化过程中表达减少。我们还发现，在长期吸烟期间，该细胞亚群向分化程度更高的细胞类型的转变程度更高，这可能会导致 IL-33 的减少。蛋白质分析表明，与以前吸烟的慢性阻塞性肺病患者相比，当前吸烟者的肺组织中 IL-33 水平较低，并且与戒烟者相比，当前吸烟者的 IL-33 阳性基底细胞比例较低。结论：我们提供了强有力的证据，表明香烟烟雾导致 IL-33 转录组和蛋白质水平表达总体降低，这可能是由于静息基底细胞的减少所致。总之，这些发现可以解释临床观察结果，即最近基于抗体的抗 IL-33 治疗对于患有慢性阻塞性肺病的吸烟者比目前吸烟者更有效。