IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels

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.

Blood Biomarkers of Emphysema: What Can They Really Tell Us?

“…Single-level transcriptomics and proteomics analyses have been used to unravel the complexity of chronic obstructive pulmonary disease (COPD) pathogenesis and treatment response ( 1 – 4 ). Thus far, resected lung tissue or bronchial biopsies and brushes have been considered to be the most relevant samples to investigate.…”

Uncovering the Complexities of IL-33 Signaling in Chronic Obstructive Pulmonary Disease

“…In this issue of the Journal , to examine potential mechanisms that may underlie these clinical findings, Faiz and colleagues (pp. 1075–1087 ) explored the expression of the IL-33 pathway in relation to smoking status in several datasets of transcriptomic analysis of lung airways ( 10 ). In bulk transcriptome studies, they found that mRNA levels of IL-33 were reduced in current smokers when compared with ex- (or never-)smokers.…”