Specific Inhibition of the NLRP3 Inflammasome as an Antiinflammatory Strategy in Cystic Fibrosis

• Published in: American journal of respiratory and critical care medicine Vol. 200; no. 11; pp. 1381 - 1391
• Main Authors: McElvaney, Oliver J., Zaslona, Zbigniew, Becker-Flegler, Katrin, Palsson-McDermott, Eva M., Boland, Fiona, Gunaratnam, Cedric, Gulbins, Erich, O’Neill, Luke A., Reeves, Emer P., McElvaney, Noel G.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.12.2019
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Biomarkers - analysis; Bronchoalveolar Lavage Fluid - chemistry; Cystic fibrosis; Cystic Fibrosis - drug therapy; Furans - therapeutic use; Gram-negative bacteria; Humans; Inflammasomes - drug effects; Inflammation; Interleukin-1beta - analysis; Lung diseases; Mice; Neutrophils - drug effects; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; Pseudomonas Infections - etiology; Pseudomonas Infections - therapy; Sulfonamides - therapeutic use; MCC950; IL-1β; NLRP3 inflammasome; neutrophils; pyruvate kinase M2
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201905-1013OC

Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with and sustained neutrophil-dominant inflammation. The lack of effective antiinflammatory therapies for people with CF (PWCF) represents a significant challenge. To identify altered immunometabolism in the CF neutrophil and investigate the feasibility of specific inhibition of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome as a CF antiinflammatory strategy . Key markers of increased aerobic glycolysis, known as a Warburg effect, including cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, succinate, HIF-1α (hypoxia-inducible factor-1α), lactate, and the IL-1β precursor pro-IL-1β, as well as caspase-1 activity and processing of pro-IL-1β to IL-1β by the NLRP3 inflammasome, were measured in neutrophils from blood and airway secretions from healthy control subjects (  = 12), PWCF (  = 16), and PWCF after double-lung transplantation (  = 6). The effects of specific inhibition of NLRP3 on airway inflammation and bacterial clearance in a murine CF model were subsequently assessed . CF neutrophils display increased aerobic glycolysis in the systemic circulation. This effect is driven by low-level endotoxemia, unaffected by CFTR (cystic fibrosis transmembrane conductance regulator) modulation, and resolves after transplant. The increased pro-IL-1β produced is processed to its mature active form in the LPS-rich CF lung by the NLRP3 inflammasome via caspase-1. Specific NLRP3 inhibition with MCC950 inhibited IL-1β in the lungs of CF mice (  < 0.0001), resulting in significantly reduced airway inflammation and improved clearance (  < 0.0001). CF neutrophil immunometabolism is altered in response to inflammation. NLRP3 inflammasome inhibition may have an antiinflammatory and anti-infective role in CF.