The role of the NLRP3 inflammasome in mucociliary clearance in bronchiectasis: The EMBARC-BRIDGE study

<b>Background:</b> Impaired mucociliary clearance is a hallmark in bronchiectasis. Excess dehydration mucus and reduced ciliary motility are believed to primarily result from excess inflammation. The inflammasome is a key regulatory complex of the inflammatory response and has not been studied in bronchiectasis. <b>Methods:</b> European Observational cohort study NCT03791086 at three centres (Dundee, Milan, Barcelona). Sputum from 269 patients with stable bronchiectasis was collected. IL-1β levels were measured in sputum supernatant to stratify patients (designated by High and Low). In an independent cohort (n=53), caspase-1 and mucus properties were studied. The ciliary beat pattern in air-liquid interface cultures was analyzed by high-speed video-microscopy with and without 100ng/ml IL-1β treatment. <b>Results:</b> Patients with high IL-1β levels had more severe disease. Caspase activity was increased in this group. Ac-YVAD-CHO, a specific caspase-1 inhibitor, reduced the activity up to 75%, indicating inflammasome activation through mainly caspase-1 and IL-1β (r_s=0.8, p&lt;0.0001). High IL-1β was associated with increased mucus solid content, suggesting mucus dehydration, and with sputum purulence. Chronic IL-1β exposure significantly reduced the beating angle and amplitude. <b>Conclusion:</b> A subset of bronchiectasis patients are characterised by inflammasome activation, high IL-1β release, mucus dehydration and ciliary dysfunction.