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. 2025 Mar 25;26(1):114.
doi: 10.1186/s12931-025-03177-x.

Lung IL-13 gene signatures are associated with raised tissue eosinophils in COPD

Karl J Staples #  1   2 , Jodie Ackland #  3 , Sruthymol Lukose  3   4 , Bastian Angermann  5 , Graham Belfield  6 , Maria Belvisi  7   8 , Raghothama Chaerkady  9 , Damla Etal  6 , Ashley Heinson  3 , Sonja Hess  9 , Ventzislava A Hristova  9 , Michael Hühn  5 , Christopher McCrae  10 , Daniel Muthas  5 , Lisa Öberg  5 , Kristoffer Ostridge  3   5 , Adam Platt  11 , C Mirella Spalluto  3 , Alastair Watson  3 , Tom Wilkinson  3   4 ; MICAII study group
Affiliations

Lung IL-13 gene signatures are associated with raised tissue eosinophils in COPD

Karl J Staples et al. Respir Res. .

Abstract

Background: The role of eosinophils in COPD and their utility as biomarkers for cytokine targeting monoclonal therapies remains unclear. We investigated the distribution of eosinophils across different tissue compartments in COPD and analysed gene expression to understand the possible mechanistic drivers of eosinophilic inflammation in COPD.

Methods: Blood and BAL from ex-smoking volunteers with mild/moderate COPD (n = 31) and healthy ex-smoking controls (n = 20), and bronchial biopsy tissue in a subcohort (n = 19 and n = 8, respectively) was analysed. Differentially-expressed genes (DEGs) were characterised using RNASeq. Proteomic analysis of BAL was conducted using mass-spectrometry.

Results: COPD subjects had more eosinophils in blood and lung tissue compared to controls, with increased eosinophil protein CLC/Galectin-10 in BAL. However, peripheral blood eosinophil counts related poorly to numbers in lung tissue (rho = -0.09192, p = 0.3541) or proportions in BAL (rho = 0.01762, p = 0.4632). Tissue IL-5Rα expression was higher in frequent exacerbators and related to tissue eosinophils, but not peripheral blood eosinophils. Higher blood eosinophils were associated with DEGs that differed with compartment. Higher tissue eosinophil levels were associated with IL-13-induced DEGs including POSTN in bronchial brushes and CCL26 in bronchial biopsies. Gene-set enrichment analysis on data from brushings revealed significant enrichment of IL-4/IL-13, but not IL-5, pathways associated with eosinophil presence.

Conclusion: Eosinophilic lung inflammation is related to exacerbation frequency, but lung eosinophils are not predicted by blood eosinophil counts in COPD. Our data suggest IL-13-mediated pathways may be responsible for the presence of tissue eosinophils in COPD. Further work to establish more predictive biomarkers of lung eosinophil biology are required to unlock this axis to optimised treatment.

Keywords: COPD; Eosinophils; Exacerbations.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Approved by and performed in accordance with National Research Ethics Service South Central ethical standards – Hampshire A and Oxford C Committees (LREC no: 15/SC/0528). All participants gave informed consent to participate in this study. Consent for publication: Not applicable. Competing interests: Dr. Öberg, Dr. Angermann, Dr. Hühn, Dr. Muthas, Dr. Etal, Dr. Hristova, Dr. Chaerkady, Dr. Hess, Dr Belfield, Dr McCrae, Dr Platt, Prof. Belvisi and Dr Ostridge are paid employees of AstraZeneca and may have stocks/stock options and/or restricted stock from AstraZeneca; Prof. Staples reports grants from AstraZeneca, during the conduct of the study; Prof. Wilkinson reports grants and personal fees from AstraZeneca, during the conduct of the study; personal fees and other from MMH, grants and personal fees from GSK, grants and personal fees from AZ, personal fees from BI, grants and personal fees from Synairgen, outside the submitted work; Dr Watson, Dr Spalluto, Dr Heinson, Dr Ackland and Dr Lukose report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Flow diagram of patient data and samples from the MICAII study. Blue box indicates data and samples used in this analysis
Fig. 2
Fig. 2
Presence of eosinophils in the lung of HV-ES and COPD subjects. A Volcano plot of BAL proteomics in HV-ES vs. COPD. B Bright-field Mayer's haematoxylin and eosin (H&E) and immunofluorescence (IF) staining for eosinophils on human lung tissue from HV-ES and COPD subjects. Images were captured using a 20 × objective on an Olympus VS110 slide scanning microscope, scale bar 50 μm. C Scatter diagram of eosinophils in the lung tissue of HV-ES and COPD subjects, quantified in cells/mm2. Statistical analysis was performed with one-tailed Mann–Whitney’s; p < 0.05*
Fig. 3
Fig. 3
Transcriptomic differences across different compartments of COPD subjects associated with blood eosinophil levels. Differential gene expression analysis compared COPD subjects with high and low blood eosinophils and identified (A) 8 DEGs in blood, (B) 21 DEGs in epithelial brushings and (C) 137 DEGs in bronchial biopsies, but no DEGS (D) were shared between sample compartments. E Enrichment analysis of DEGs derived from bronchial biopsy samples identified significant enrichment metabolic processes. Gene list enrichment using over representation analysis was performed using clusterProfiler. In (E) only the top 5 significantly enriched (adjusted p-value < 0.05) terms and/or pathways are visualised and are ordered by enrichment significance
Fig. 4
Fig. 4
Transcriptomic differences across different compartments of COPD subjects associated with tissue eosinophil levels Differential gene expression analysis on the immunofluorescence (IF) sub cohort compared COPD subjects with high and low tissue eosinophil levels and found (A) 5 DEGs in blood, (B) 13 DEGs in bronchial biopsies and (C) 32 DEGs in epithelial brushings, and very few DEGS (D) were shared between sample compartments. (E) Gene set enrichment analysis (GSEA) on the IF subcohort ranked epithelial brushings gene list identified positive significant enrichment of the REACTOME IL-4/IL-13 pathway (R-HSA-6785807). GSEA was performed using clusterProfiler. NES = normalised enrichment score.
Fig. 5
Fig. 5
Tissue IL5Rα expression and associations with tissue eosinophils. A Bright-field Mayer's haematoxylin and eosin (H&E) and IF staining for IL5Rα on human lung tissue from HV-ES and COPD subjects. Images were captured using a 20 × objective on an Olympus VS110 slide scanning microscope, scale bar 50 μm. B Spearman’s non-parametric correlation between eosinophils and IL5Rα in the lung tissue of COPD subjects. C IL5Rα in the lung tissue of COPD subjects with tissue eosinophil count below 200 cell/mm2 and above 200 cells/mm2. D Distribution of IL5Rα in lung tissue of COPD subjects separated into infrequent (P-IE) and frequent exacerbators (P-FE) phenotype. E Eosinophils in the lung tissue of COPD subjects with P-IE and P-FE phenotype. Two-tailed Mann–Whitney’s statistical analysis was performed; p < 0.05*
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