Epithelial Cell-Derived IL-25, but Not Th17 Cell-Derived IL-17 or IL-17F, Is Crucial for Murine Asthma

Abstract

IL-17A, IL-17F and IL-25 are ligands for IL-17RA. In the present study, we demonstrated that IL-25-deficient mice, but not IL-17A-, IL-17F-, IL-17A/F-, IL-23p19- and ROR-γt-deficient mice, showed significant suppression of the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, airway hyperresponsiveness to methacholine, or ovalbumin-specific IgG1 and IgE levels in the serum during ovalbumin-induced Th2-type/eosinophilic airway inflammation, without any effect on lung DC migration or antigen-specific memory-Th2-cell expansion during antigen sensitization. By adoptive transfer of either T cells, mast cells or bone marrow cells from IL-25-deficient mice, we found that IL-25 produced by airway structural cells such as epithelial cells—but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells—was indispensable for induction of Th2-type/eosinophilic airway inflammation by activating lung epithelial cells and eosinophils. Therefore, airway structural-cell-derived IL-25—rather than Th17-cell-derived IL-17A and IL-17F—is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase—but is not required for antigen-specific Th2 cell differentiation in the sensitization phase—of Th2-type/eosinophilic airway inflammation.

Poly(inosinic-cytidylic) Acid–Triggered Exacerbation of Experimental Asthma Depends on IL-17A Produced by NK Cells

“…IL-23 expression is elevated in mice with experimental asthma and exogenous administration or local overexpression of IL-23 resulted in aggravation of the disease (42,43). In contrast, lack of IL-23 had no effect on the development of experimental asthma in mice (34). The latter study is in line with our results, whereas IL23p19 (46), and NK cells (47).…”

“…On the one hand, in adjuvant-free mouse models, IL-17A seems to be required for the sensitization against an allergen and the initiation of Ag-mediated airway inflammation (25,33). On the other hand, IL-17A deficiency had no significant effect on sensitization or the phenotype of experimental asthma, if mice were sensitized systemically by using an adjuvant (34). The results of our experiments are in line with that latter study and display that IL-17A is not required for the development of experimental allergic asthma.…”

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

“…Eosinophilic airway inflammation and airway remodeling are common features of asthma and IL-25 can induce these abnormalities in animal models (18,27). We found that IL-25-high subjects with asthma had more marked eosinophilic airway inflammation, as reflected by higher levels of eosinophils in both sputum and airway submucosa from airway biopsies ( Figures 3A and 3B).…”

“…The epithelial cytokines IL-25 and IL-33 act on multiple immune cells, including mast cells, basophils, and iLC2s (12)(13)(14)(15)(16)(17). IL-25 (18)(19)(20)(21), IL-33 (22), and TSLP (11) have each been reported to be both necessary and sufficient for type 2 cytokine production, eosinophilic airway inflammation, mucous metaplasia, and airway hyperresponsiveness in certain mouse models. In human studies, bronchial expression of TSLP (23), IL-25 (24,25), and IL-33 (26) have been reported to be increased in asthma.…”

Evaluation of protective and pathological immune response against chlamydial infection and re-infection in mice

“…It was reported earlier that the production of IL-17E by T cells, mast cells and other haematopoietic immune cells is not essential for the development of Th2-type/eosinophilic airway inflammation, suggesting that the IL-17E produced by non-immune cells such as airway epithelial cells, is crucial for its development 83 . We found that the epithelial cells of the lung are responsible for the production of IL-17E in the later stages of pulmonary C. muridarum infection.…”