Abstract
Rationale The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1[3 [3 (IL-1[3) [3 ) release and activation. IL-1[3 [3 amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1[3 [3 in bronchiectasis has not been investigated. Objectives To characterise the role of airway IL-1[3 [3 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-1[3 [3 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-1[3 [3 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 - liquid interface culture were used to study the effect of IL-1[3 [3 on cilia function. Results Patients with high sputum IL-1[3 [3 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-1[3. [3 . The active-dominant form of IL-1[3 [3 was associated with increased disease severity. High IL-1[3 [3 was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1[3 [3 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-1[3, [3 , suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.