Abstract
BackgroundEosinophil-lineage committed progenitor cells (EoP) migrate from the bone marrow and differentiate locally to provide an ongoing source of mature eosinophils in asthmatic inflammatory responses in the airways. Sputum levels of EoP are increased in asthmatics compared to normal controls suggesting an exaggerated eosinophilopoietic environment in the airways. Understanding what factors promote EoP traffic to the airways is important to understand the diathesis of asthma pathology. Interleukin (IL)-25, is an epithelial-derived cytokine that promotes type 2 inflammatory responses. We have previously shown that levels of IL-25 and expression of the IL-25 receptor (IL-17RA and IL-17RB) on mature eosinophils are greater in allergic asthmatics compared to atopic non-asthmatics and non-atopic normal controls. In addition, these levels were increased significantly increased following allergen inhalation challenge and physiologically relevant levels of IL-25 stimulated eosinophil degranulation, intracellular IL-5 and IL-13 expression and primed migration to eotaxin. The current study, examined the role of IL-25 on allergen-induced trafficking of EoP in atopic asthmatics.MethodsAsthmatics (n = 14) who developed allergen-induced early and late responses were enrolled in the study. Blood was collected at pre- and 24 h post-challenge. At each time point, surface expression of IL-17RA and IL-17RB on EoP was evaluated by flow cytometry. Migration assays examined the effect of IL-25 on EoP chemotactic responses, in vitro. In addition, IL-25 knockout ovalbumin (OVA) sensitized and challenged mice were studied to evaluate in vivo mobilization effects of IL-25 on newly formed EoP and mature eosinophils.ResultsThere was a significant increase in numbers of blood EoP expressing IL-17RB, 24 h post-allergen inhalation challenge in allergic asthmatics. Pre-exposure to IL-25 primed the migrational responsiveness of EoP to stromal cell-derived factor 1α. In OVA-sensitized mice, knocking out IL-25 significantly alleviated OVA-induced eosinophil infiltration in the airway and newly formed eosinophils were reduced in the lung.ConclusionsThe findings of this study indicate a potential role for IL-25 in allergen-induced trafficking of EoP to the airways and local differentiation promoting tissue eosiniophilia in asthmatic responses.
Highlights
Eosinophil-lineage committed progenitor cells (EoP) migrate from the bone marrow and differentiate locally to provide an ongoing source of mature eosinophils in asthmatic inflammatory responses in the airways
Following allergen inhalation challenge, all asthmatic subjects developed an early and late bronchoconstrictor responses; the maximal early fall in FEV1 was 33.67 + 8.22% and the maximal late fall in FEV1 (3–7 h post-allergen inhalation) was 22.47 + 8.43% (Table 2). This was associated with a significant increase airway eosinophilia (Table 2) and total number of number of blood hemopoietic progenitor cells (HPC) and EoP (HPC: 1663 ± 657 vs. 723 ± 244 per 1 06 WBC, p < 0.01; EoP: 1188 ± 442 vs. 519 ± 140 per 106 WBC, p < 0.01) 24 h post-allergen compared to pre-allergen levels
We found that IL-25 over a wide concentration range (0.1 – 1000 pg/ml) has no effect on the migrational responses of EoP compared to diluent control, in vitro
Summary
Eosinophil-lineage committed progenitor cells (EoP) migrate from the bone marrow and differentiate locally to provide an ongoing source of mature eosinophils in asthmatic inflammatory responses in the airways. We have previously shown that levels of IL-25 and expression of the IL-25 receptor (IL-17RA and IL-17RB) on mature eosinophils are greater in allergic asthmatics compared to atopic non-asthmatics and non-atopic normal controls. These levels were increased significantly increased following allergen inhalation challenge and physiologically relevant levels of IL-25 stimulated eosinophil degranulation, intracellular IL-5 and IL-13 expression and primed migration to eotaxin. In a previous baseline cross-sectional study, we have shown significantly increased expression of IL-17RA and IL-17RB on mature eosinophils and plasma levels of IL-25 in asymptomatic mild allergic asthmatics compared with atopic non-asthmatics and non-atopic normal subjects [6]. In vitro experiments showed that at physiologically relevant concentrations, IL-25 stimulated eosinophil degranulation and primed the migrational responses of mature eosinophils
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