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

Abstract

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