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

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. 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. Human airway epithelial cells (AECs) grown from non-CF and CF cell lines and and mice were used in this study. Pulmonary inflammation in and mice with and without IL-33 or ST2 (IL-1 receptor-like 1) germline deletion was determined by histological analysis, BAL, and cytokine analysis. After allergen challenge, both CF human AECs and mice had increased IL-33 expression compared with control AECs and mice, respectively. DUOX1 (dual oxidase 1) expression was increased in CF human AECs and mouse lungs compared with control AECs and lungs from mice and was necessary for the increased IL-33 release in mice compared with mice. IL-33 stimulation of CD4 T cells resulted in increased type 2 cytokine production compared with CD4 T cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in mice compared with mice. 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.