Lydia Becker Institute for Immunology & Infection, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
PLoS Pathog. 2018 Nov 30;14(11):e1007423. doi: 10.1371/journal.ppat.1007423. eCollection 2018 Nov.
Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.
Ym1 和 RELMα 是与 Th2 型炎症和相关病理学密切相关的已确定效应分子。在这里,我们表明,尽管在 2 型反应中主要依赖于 IL-4Rα 信号,但 Ym1 和 RELMα 在肺部也具有 IL-4Rα 非依赖性表达模式。值得注意的是,我们发现 Ym1 在寄生虫感染期间对 2 型免疫具有相反的影响,具体取决于它是在先天还是适应性反应时表达。在巴西旋毛虫的肺部迁移阶段,Ym1 促进了随后的修复性 2 型反应,但一旦该反应建立,IL-4Rα 依赖性 Ym1 对于限制肺部 CD4+T 细胞和固有淋巴细胞中 2 型细胞因子产生的幅度非常重要。重要的是,我们的研究表明,将 Ym1 递送到 IL-4Rα 缺陷动物中会驱动 RELMα 的产生,并克服 2 型免疫缺陷小鼠的肺部修复缺陷。总之,Ym1 和 RELMα 表现出时间和剂量依赖性相互作用,决定了寄生虫感染期间肺部修复的结果。
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