Inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma.

Autor: Chen L; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., A Hoefel G; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Pathinayake PS; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia., Reid A; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia., Pillar AL; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Kelly C; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Tan H; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Ali A; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Kim RY; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia., Hansbro PM; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, New South Wales, Australia., Brody SL; Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri, USA., Foster PS; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Horvat JC; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Riveros C; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Awatade N; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia., Wark PAB; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton, New South Wales, Australia.; Department of Respiratory Medicine, Alfred Health, Melbourne, Victoria, Australia., Kaiko GE; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.; Immune Health Program, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Respirology (Carlton, Vic.) [Respirology] 2024 Oct 02. Date of Electronic Publication: 2024 Oct 02.
DOI: 10.1111/resp.14833
Abstrakt: Background and Objective: Severe asthma is a heterogeneous disease with subtype classification according to dominant airway infiltrates, including eosinophilic (Type 2 high), or non-eosinophilic asthma. Non-eosinophilic asthma is further divided into paucigranulocytic or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in the airways. Severe non-eosinophilic asthma has few effective treatments and many patients do not qualify for biologic therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease and has proven a valuable therapeutic target. We hypothesized that the CFTR may also play a role in non-eosinophilic asthma.
Methods: Patient-derived human bronchial epithelial cells (hBECs) were isolated and differentiated at the air-liquid interface. Single cell RNA-sequencing (scRNAseq) was used to identify epithelial cell subtypes and transcriptional activity. Ion transport was investigated with Ussing chambers and immunofluorescent quantification of ionocyte abundance in human airway epithelial cells and murine models of asthma.
Results: We identified that hBECs from patients with non-eosinophilic asthma had reduced CFTR function, and did not differentiate into CFTR-expressing ionocytes compared to those from eosinophilic asthma or healthy donors. Similarly, ionocytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic asthma. Treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture led to a reduction in ionocytes.
Conclusion: Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target.
(© 2024 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)
Databáze: MEDLINE
Externí odkaz: