Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD

Faiz, Alen; Pavlidis, Stelios; Kuo, Chih-Hsi S.; Rowe, Anthony; Hiemstra, Pieter S.; Timens, Wim; Berg, Marijn; Wisman, Marissa; Guo, Yike; Djukanović, Ratko; Sterk, Peter J.; Meyer, Kerstin B.; Nawijn, Martijn C.; Adcock, Ian M.; Chung, Kian Fan; Berge, Maarten van den

doi:10.1136/thorax-2021-217736

Cited by 14 publications

(11 citation statements)

References 34 publications

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“…A Uniform Manifold Approximation and Projection (UMAP) and violin plot show that the majority of IL-33 –expressing cells are resting basal cells and endothelial cells ( Figure 4A and Figure E5A). Although IL1RL1 was found to be expressed mainly in mast cells, mirroring a previous report ( 44 ), it was also present in the endothelial aerocyte capillary cells ( Figure 4B and see Figure E5B), whereas IL1RAP was mainly in monocytes ( see Figure E5C). Based on this finding, we conducted cellular deconvolution to examine the association between smoking status and cellular composition.…”

Section: Resultssupporting

confidence: 88%

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

Faiz,

Mahbub,

Boedijono

et al. 2023

Am J Respir Crit Care Med

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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.

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Section: Resultssupporting

confidence: 88%

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

Faiz,

Mahbub,

Boedijono

et al. 2023

Am J Respir Crit Care Med

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“…Transcriptome analysis of bronchial biopsies collected during the GLUCOLD clinical trial reported increased T2-related gene expression in a subset of COPD patients with increased blood and lung eosinophil numbers, which was associated with increased ICS responsiveness [ 106 ]. A subsequent analysis of the GLUCOLD data, using hierarchical clustering of genes previously defined using severe asthma sputum samples, identified subgroups of COPD patients with different transcriptome signatures associated with T2 inflammation, inflammasome activation or mitochondrial activation [ 107 ]. Following ICS intervention, only the T2 signature was supressed.…”

Section: Eosinophils Type 2 Inflammation and Corticosteroid Response ...mentioning

confidence: 99%

How inhaled corticosteroids target inflammation in COPD

Lea,

Higham,

Beech

et al. 2023

Eur Respir Rev

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Inhaled corticosteroids (ICS) are the most commonly used anti-inflammatory drugs for the treatment of COPD. COPD has been previously described as a “corticosteroid-resistant” condition, but current clinical trial evidence shows that selected COPD patients, namely those with increased exacerbation risk plus higher blood eosinophil count (BEC), can benefit from ICS treatment. This review describes the components of inflammation modulated by ICS in COPD and the reasons for the variation in response to ICS between individuals. There are corticosteroid-insensitive inflammatory pathways in COPD, such as bacteria-induced macrophage interleukin-8 production and resultant neutrophil recruitment, but also corticosteroid-sensitive pathways including the reduction of type 2 markers and mast cell numbers. The review also describes the mechanisms whereby ICS can skew the lung microbiome, with reduced diversity and increased relative abundance, towards an excess of proteobacteria. BEC is a biomarker used to enable the selective use of ICS in COPD, but the clinical outcome in an individual is decided by a complex interacting network involving the microbiome and airway inflammation.

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“…Furthermore, recent findings by F aiz et al . [ 15 ] through gene expression profiling studies in large airway bronchial biopsies and sputum of moderate-to-severe COPD patients showed an association of MC tryptase and chymase as critical drivers of COPD pathology, with increased suppression seen in the inhaled corticosteroid-treated group of patients. A similar association was also drawn between MC gene expression in the eosinophil high subpopulation of COPD patients [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD

Eapen,

Lu,

Dey

et al. 2024

ERJ Open Res

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BackgroundCOPD patients suffer from dysregulated and suppressed immune functionality, determined by their loss of degranulating capacity. Here we provide crucial information on the presence of degranulated MC in COPD airways and demonstrate their relationship to lung physiology and airway remodelling.MethodsSmall airway (SA) lung resections from non-smoking controls (NC), smokers with normal lung function (NLFS), small airway disease (SAD), mild-moderate COPD current smokers (CS), and ex-smokers (ES) were dual immuno-stained with mast cell tryptase and degranulation marker LAMP-1. Total MC, degranulating MC and non-MC were enumerated in SA epithelium and sub-epithelium, respectively, and in alveolar septa.ResultsIn the SA wall, sub-epithelial areas, COPD-CS and -ES had significantly lower mast cells than NC (p<0.05), though considerably higher in SA epithelium (p<0.01). Degranulating non-mast cells were higher in SAD (p<0.05) than in COPD in SA sub-epithelium. In contrast, there were significant increases in total mast cells (degranulated and non-degranulated) and degranulated non-mast cells in the alveolar septum of COPD patients compared to NC (p<001). The lower numbers of mast cells in the sub-epithelium correlated with lower FEV1/FVC and FEF25-75%, higher smoking rates in COPD patients, and increased SA wall thickness and ECM. The increase in the alveolar in mast cells negatively correlated with FEF 25-75%.ConclusionsThis study is the first to assess the differential pattern of mast cells, degranulating mast and non-mast cell populations in the SA and alveoli of COPD patients. The spatial positioning of the mast cells within the airways showed variable correlations with lung function.

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Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD

Cited by 14 publications

References 34 publications

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

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

How inhaled corticosteroids target inflammation in COPD

Differential expression of mast cells in the small airways and alveolar septa of current smokers and patients with small airway disease and COPD

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