Rationale: Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with Pseudomonas aeruginosa and sustained neutrophil-dominant inflammation. The lack of effective antiinflammatory therapies for people with CF (PWCF) represents a significant challenge. Objectives: 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 in vivo. Methods: 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 (n = 12), PWCF (n = 16), and PWCF after double-lung transplantation (n = 6). The effects of specific inhibition of NLRP3 on airway inflammation and bacterial clearance in a murine CF model were subsequently assessed in vivo.Measurements and Main Results: 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 in vivo with MCC950 inhibited IL-1β in the lungs of CF mice (P < 0.0001), resulting in significantly reduced airway inflammation and improved Pseudomonas clearance (P < 0.0001).Conclusions: CF neutrophil immunometabolism is altered in response to inflammation. NLRP3 inflammasome inhibition may have an antiinflammatory and anti-infective role in CF.
Rationale: Cystic fibrosis (CF) pulmonary disease is characterized by chronic infection with Pseudomonas aeruginosa and sustained neutrophil-dominant inflammation. The lack of effective antiinflammatory therapies for people with CF (PWCF) represents a significant challenge. Objectives: 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 in vivo. Methods: 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 (n = 12), PWCF (n = 16), and PWCF after double-lung transplantation (n = 6). The effects of specific inhibition of NLRP3 on airway inflammation and bacterial clearance in a murine CF model were subsequently assessed in vivo.Measurements and Main Results: 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 in vivo with MCC950 inhibited IL-1β in the lungs of CF mice (P < 0.0001), resulting in significantly reduced airway inflammation and improved Pseudomonas clearance (P < 0.0001).Conclusions: CF neutrophil immunometabolism is altered in response to inflammation. NLRP3 inflammasome inhibition may have an antiinflammatory and anti-infective role in CF.
Authors: Jonas C Schupp; Sara Khanal; Jose L Gomez; Maor Sauler; Taylor S Adams; Geoffrey L Chupp; Xiting Yan; Sergio Poli; Yujiao Zhao; Ruth R Montgomery; Ivan O Rosas; Charles S Dela Cruz; Emanuela M Bruscia; Marie E Egan; Naftali Kaminski; Clemente J Britto Journal: Am J Respir Crit Care Med Date: 2020-11-15 Impact factor: 21.405
Authors: Ellen McKenna; Richard Wubben; Johana M Isaza-Correa; Ashanty M Melo; Aisling Ui Mhaonaigh; Niall Conlon; James S O'Donnell; Clíona Ní Cheallaigh; Tim Hurley; Nigel J Stevenson; Mark A Little; Eleanor J Molloy Journal: Front Immunol Date: 2022-06-01 Impact factor: 8.786
Authors: Andrew D Graustein; William R Berrington; Kati J Buckingham; Felicia K Nguyen; Lara L Joudeh; Margaret Rosenfeld; Michael J Bamshad; Ronald L Gibson; Thomas R Hawn; Mary J Emond Journal: Am J Respir Cell Mol Biol Date: 2021-08 Impact factor: 6.914
Authors: Lael M Yonker; Anika Marand; Sinan Muldur; Alex Hopke; Hui Min Leung; Denis De La Flor; Grace Park; Hanna Pinsky; Lauren B Guthrie; Guillermo J Tearney; Daniel Irimia; Bryan P Hurley Journal: J Cyst Fibros Date: 2021-02-13 Impact factor: 5.482
Authors: Mariángeles Clauzure; Ángel G Valdivieso; Andrea V Dugour; Consuelo Mori; María M Massip-Copiz; María Á Aguilar; Verónica Sotomayor; Cristian J A Asensio; Juan M Figueroa; Tomás A Santa-Coloma Journal: Immunology Date: 2021-05-02 Impact factor: 7.215