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

• Published in: Respirology (Carlton, Vic.) Vic.), 2024-10, Vol.30 (1), p.25-40
• Main Authors: Chen, Ling, A. Hoefel, Gabriela, Pathinayake, Prabuddha S., Reid, Andrew, Pillar, Amber L., Kelly, Coady, Tan, HuiYing, Ali, Ayesha, Kim, Richard Y., Hansbro, Philip M., Brody, Steven L., Foster, Paul S., Horvat, Jay C., Riveros, Carlos, Awatade, Nikhil, Wark, Peter A. B., Kaiko, Gerard E.
• Format: Article
• Language: English
• Subjects: airway epithelium; Animal models; Asthma; Cell culture; Cell differentiation; CFTR; Chronic obstructive pulmonary disease; Cystic fibrosis; Cytokines; Disease; Epithelial cells; Inflammation; ionocytes; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lung diseases; mucous; neutrophils; Respiratory diseases; Respiratory tract diseases; severe asthma; single cell RNA‐sequencing; Therapeutic targets
• ISSN: 1323-7799; 1440-1843; 1440-1843
• DOI: 10.1111/resp.14833

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. We demonstrate reduced CFTR function, CFTR protein‐expressing cells and airway ionocytes in non‐eosinophilic severe asthma in the setting of a Type 1/Type 17 cytokine environment. This suggests a role for dysfunction in the CFTR pathway applicable to other chronic neutrophil‐dominant airways diseases, including subtypes of asthma. See related editorial