Epithelial cells play an important role in orchestrating mucosal immune responses. In allergic-type inflammation, epithelial cells control the recruitment of eosinophils into the mucosa. Th2-type cytokine-driven release of eosinophil-active chemokines from epithelial cells directs eosinophil migration into the mucosal epithelium. CCR3, the main eosinophil chemokine receptor, regulates this process; however, the respective contribution of individual CCR3 ligands in eosinophil transepithelial migration is less well understood. Using an in vitro transepithelial chemotaxis system, we found that eotaxin-3 produced by IL-4-stimulated airway epithelial cells and CCR3 on eosinophils exclusively mediate eosinophil transepithelial migration. Eotaxin-3 protein levels were also increased in the nasal mucosal epithelium recovered from allergic patients as compared to non-allergic patients. Surprisingly, eotaxin-3 in IL-4-stimulated airway epithelial cells was predominantly cell surface bound, and the cell surface form was critical for eosinophil transepithelial migration. Eotaxin-3 cell surface association was partially glycosaminoglycan (GAG) dependent, but was completely protein dependent, suggesting that eotaxin-3 associates with both GAG and cell surface proteins. We thus provide evidence that cell surface-associated eotaxin-3 is the critical IL-4-dependent chemotactic signal mediating eosinophil transepithelial migration in the setting of allergic inflammation.

译文

:上皮细胞在协调粘膜免疫反应中起重要作用。在过敏型炎症中,上皮细胞控制嗜酸性粒细胞向粘膜的募集。 Th2型细胞因子驱动的嗜酸性粒细胞活性趋化因子从上皮细胞的释放引导嗜酸性粒细胞迁移到粘膜上皮中。 CCR3是主要的嗜酸性粒细胞趋化因子受体,调节这一过程。然而,单个CCR3配体在嗜酸性粒细胞上皮细胞迁移中的各自作用尚不清楚。使用体外经上皮趋化系统,我们发现由IL-4刺激的气道上皮细胞和嗜酸性粒细胞上的CCR3产生的eotaxin-3专门介导嗜酸性粒细胞跨上皮迁移。与非过敏患者相比,从过敏患者中回收的鼻粘膜上皮中的Eotaxin-3蛋白水平也有所增加。出人意料的是,IL-4刺激的气道上皮细胞中的eotaxin-3主要与细胞表面结合,并且细胞表面形式对于嗜酸性粒细胞跨上皮迁移至关重要。 Eotaxin-3细胞表面缔合部分依赖糖胺聚糖(GAG),但完全依赖蛋白质,这表明eotaxin-3与GAG和细胞表面蛋白缔合。因此,我们提供证据,在过敏性炎症的情况下,细胞表面相关的eotaxin-3是介导嗜酸性粒细胞跨上皮迁移的关键IL-4依赖性趋化信号。

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