Cystic Fibrosis Reprograms Airway Epithelial IL-33 Release and Licenses IL-33–Dependent Inflammation
Daniel P. Cook, Christopher M. Thomas, Ashley Y. Wu, Mark Rusznak, Jian Zhang, Weisong Zhou, Jacqueline-Yvonne Cephus, Katherine N. Gibson‐Corley, Vasiliy V. Polosukhin, Allison E. Norlander, Dawn C. Newcomb, David A. Stoltz, R. Stokes Peebles
Abstract
Abstract Rationale Type 2 inflammation has been described in people with cystic fibrosis (CF). Whether loss of CFTR (cystic fibrosis transmembrane conductance regulator) function contributes directly to a type 2 inflammatory response has not been fully defined. Objectives The potent alarmin IL-33 has emerged as a critical regulator of type 2 inflammation. We tested the hypothesis that CFTR deficiency increases IL-33 expression and/or release and deletion of IL-33 reduces allergen-induced inflammation in the CF lung. Methods Human airway epithelial cells (AECs) grown from non-CF and CF cell lines and Cftr +/+ and Cftr −/− mice were used in this study. Pulmonary inflammation in Cftr +/+ and Cftr −/− mice with and without IL-33 or ST2 (IL-1 receptor-like 1) germline deletion was determined by histological analysis, BAL, and cytokine analysis. Measurements and Main Results After allergen challenge, both CF human AECs and Cftr −/− mice had increased IL-33 expression compared with control AECs and Cftr +/+ mice, respectively. DUOX1 (dual oxidase 1) expression was increased in CF human AECs and Cftr −/− mouse lungs compared with control AECs and lungs from Cftr +/+ mice and was necessary for the increased IL-33 release in Cftr −/− mice compared with Cftr +/+ mice. IL-33 stimulation of Cftr −/− CD4+ T cells resulted in increased type 2 cytokine production compared with Cftr+/+ CD4+ T cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in Cftr −/− mice compared with Cftr +/+ mice. Conclusions Absence of CFTR reprograms airway epithelial IL-33 release and licenses IL-33–dependent inflammation. Modulation of the IL-33/ST2 axis represents a novel therapeutic target in CF type 2–high and neutrophilic inflammation.