Cystic Fibrosis Reprograms Airway Epithelial IL-33 Release and Licenses IL-33-Dependent Inflammation

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.