Graphical abstract
Overview of the study. BSI: Bronchiectasis Severity Index; FEV1: forced expiratory volume in 1 s; IL: interleukin; Th1: T-helper type 1; Th2: T-helper type 2. #: data confirmed in a validation cohort.
Abstract
Rationale The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1β (IL-1β) release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated.
Objectives To characterise the role of airway IL-1β in bronchiectasis, including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity.
Methods Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (high versus low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air–liquid interface culture were used to study the effect of IL-1β on cilia function.
Results Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and an increased T-helper type 1, T-helper type 2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in vitro.
Conclusions A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.
Shareable abstract
Airway IL-1β is a marker of severe disease, mucus hyperconcentration, Proteobacteria-dominant microbiome and Th1, Th2 and neutrophilic inflammation in bronchiectasis patients. In vitro, IL-1β directly impairs cilia function and epithelial integrity. https://bit.ly/4aeooF7
Footnotes
Ethics statement: All patients signed an informed consent form, and the study was approved by the local ethics committee at each participating centre (18/LO/1935).
Author contributions: Study conception and design: L. Perea, M. Bottier, M. Shteinberg, P.C. Goeminne, E. Polverino, J. Altenburg, F. Blasi, T. Welte, S. Aliberti, O. Sibila, J.D. Chalmers and A. Shoemark. Data collection: L. Perea, M. Bottier, E. Cant, H. Richardson, A.J. Dicker, M. Shuttleworth, Y.H. Giam, H. Abo-Leyah, S. Finch, J.T-J. Huang, O. Sibila, J.D. Chalmers and A. Shoemark. Laboratory work: L. Perea, M. Bottier, E. Cant, H. Richardson, A.J. Dicker, M. Shuttleworth, Y.H. Giam, S. Finch, J.T-J. Huang and A. Shoemark. Data analysis: L. Perea, J.T-J. Huang, J.D. Chalmers and A. Shoemark. Writing of the manuscript: L. Perea, J.D. Chalmers and A. Shoemark. Revising critically for important intellectual content and final approval: all authors.
This article has an editorial commentary: https://doi.org/10.1183/13993003.00997-2024
Conflict of interest: M. Shteinberg reports consulting fees from GSK, Boehringer Ingelheim, Kamada and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, Boehringer Ingelheim, GSK, AstraZeneca, Teva, Novartis, Kamada and Sanofi; support for attending meetings and/or travel from Novartis, Actelion, Boehringer Ingelheim, GSK and Rafa; participation on a data safety monitoring board or advisory board for Bonus Therapeutics, Israel; leadership roles for EMBARC Management, Israel Pulmonology Society Board, Israel Society for TB and Mycobacterial Diseases; receipt of equipment, materials, drugs, medical writing, gifts or other services from Trudell Medical Int; and is an associate editor of the American Journal of Respiratory and Critical Care Medicine. P.C. Goeminne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Insmed, GSK and Chiesi; support for attending meetings and/or travel from Chiesi; and participation on a data safety monitoring board or advisory board for Boehringer, GSK and Pfizer. E. Polverino reports grants or contracts from Grifols; consulting fees from Insmed, Bayer, Chiesi and Zambon; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Chiesi, Grifols, GSK, Insmed, Menarini and Zambon; and support for attending meetings and/or travel from Insmed, Pfizer and Moderna. F. Blasi reports grants or contracts from AstraZeneca, Chiesi and Insmed; consulting fees from Menarini; and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Chiesi, GSK, Guidotti, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Viatris, Vertex and Zambon. S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher and Paykel and GSK; royalties or licences from McGraw Hill; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Ltd, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MCD Italis SrL, Brahms, Physioassist SAS and GSK SpA; payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK SpA, Thermofisher Scientific, Insmed Italy, Insmed Ireland, Zambon and Fondazione Internazionale Menarini; and participation on a data safety monitoring board or advisory board for Insmed Incorporated, Insmed Italy, AstraZeneca UK Ltd and MSD Italia SrL. J.D. Chalmers reports grants or contracts from AstraZeneca, Boehringer Ingelheim, Genentech, Gilead Sciences, GSK, Grifols, Insmed, LifeArc and Novartis; and consulting fees from AstraZeneca, Chiesi, GSK, Insmed, Grifols, Novartis, Boehringer Ingelheim, Pfizer, Janssen, Antabio and Zambon. A. Shoemark reports consulting fees from Spirovant and Translate Bio; payment or honoraria for lectures, presentations, manuscript writing or educational events from Translate Bio, Ethris and Insmed; and a leadership role in European Respiratory Society Clinical Research Collaborations (EMBARC, BEATPCD, AMR). The remaining authors have no potential conflicts of interest to disclose.
Support statement: Research supported by the European Respiratory Society through the EMBARC2 consortium and through the long-term research fellowship to L. Perea. EMBARC2 is supported by project partners AstraZeneca, Chiesi, Grifols, Insmed, Janssen, Novartis and Zambon. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received November 6, 2023.
- Accepted May 8, 2024.
- Copyright ©The authors 2024. For reproduction rights and permissions contact permissions{at}ersnet.org
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