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 cystic fibrosis transmembrane conductance regulator (CFTR) 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/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 germline deletion was determined by histological analysis, bronchoalveolar lavage (BAL) and cytokine analysis. Measurements and Main Results: Following allergen challenge, CF human AECs and Cftr-/- mice had increased IL-33 expression compared to control AECs and Cftr+/+ mice, respectively. DUOX-1 expression was increased in CF human AECs and Cftr-/- mouse lungs compared to control AECs and lungs from Cftr+/+ mice and was necessary for the increased IL-33 release in Cftr-/- mice compared Cftr+/+ mice. IL-33 stimulation of Cftr-/- CD4+ cells resulted in increased type 2 cytokine production compared to Cftr+/+ CD4+ cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in Cftr-/- mice compared to 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.