Epithelial Interleukin-25 Is a Key Mediator in Th2-High, Corticosteroid-Responsive Asthma

Abstract

Rationale: Activation of type 2 cytokine pathways plays a central role in a large subset of subjects with asthma. Th2-high and Th2-low asthma have distinct clinical, pathologic, and molecular phenotypes and respond differently to therapy. The factors that initiate type 2 responses in some subjects with asthma are unknown.Objectives: To determine whether expression of epithelial cytokines IL-25, IL-33, and thymic stromal lymphopoietin are associated with type 2 responses and predict response to inhaled corticosteroid (ICS) in asthma.Methods: We analyzed pulmonary function tests, blood, and bronchoscopic biopsies from 21 healthy control subjects and 43 subjects with asthma. Subjects with asthma underwent an 8-week treatment with inhaled budesonide.Measurements and Main Results: Epithelial expression of IL-25, but not IL-33 or thymic stromal lymphopoietin, was increased in a subset of subjects with asthma. The IL-25-high subset had greater airway hyperresponsiveness, more airway and blood eosinophils, higher serum IgE, more subepithelial thickening, and higher expression of Th2 signature genes. ICS improved FEV 1 and hyperresponsiveness in the IL-25-high but not the IL-25-low subset. Plasma IL-25 levels correlated with epithelial IL-25 expression, airway eosinophilia, and beneficial responses to ICS treatment.Conclusions: IL-25 measurements identify two subsets of subjects with distinct asthma phenotypes and different responses to ICS. Because IL-25 has a major role in triggering type 2 responses, bronchial epithelial IL-25 expression is likely a key determinant of type 2 response activation in asthma. Plasma IL-25 level reflects airway IL-25/type 2 response activation and may be useful for predicting responses to asthma therapy.

Impact of Age and Sex on Response to Asthma Therapy

“…Exhaled nitric oxide was slightly lower in the older age group, although this small difference is not likely clinically relevant. More recently recognized Th2 biomarkers, such as periostin, DPP4, and interleukins (in both serum and bronchoalveolar lavage) (33,34), may help further delineate if older subjects with asthma have less active Th2-driven inflammation and thus potentially a reduced response to ICS.…”

Cross-Talk between Epithelial Cells and Type 2 Immune Signaling. The Role of IL-25

“…However, others have reported that airway epithelial cells from subjects with asthma express higher than normal levels of IL-25, which can be induced further by rhinovirus infection (12). Still others have found increased systemic levels of IL-25 in subgroups of patients with asthma with T helper type 2 high asthma (14). Further work is needed to elucidate more clearly the role of IL-25 in human asthma, as well as any potential participation by tuft cells, particularly in the lung, where the differentiation of epithelial cells from precursors differs markedly from the relatively linear and short-lived (3-5 d) process that occurs in the intestines (15).…”

Increased Levels of Interleukin-33 and Thymic Stromal Lymphopoietin in Exhaled Breath Condensate in Chronic Bronchial Asthma

“…IL-33 expression by epithelial cells and smooth muscle cells has also been observed in bronchial asthma [13,14]. IL-25 epithelial expression is increased in patients with asthma and it is associated with the Th2 response [15]. …”