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.