A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation
A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation
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DOI：
10.1073/pnas.0607863103
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发表时间：
2006-10-31
影响因子：
11.1
通讯作者：
Rothenberg, Marc E.
中科院分区：
文献类型：
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作者：
Fulkerson, Patricia C.;Fischetti, Christine A.;Rothenberg, Marc E.
为了阐明嗜酸性粒细胞的作用和调节，我们将几只关键的嗜酸性粒细胞相关的基因工程小鼠置于过敏性气道炎症的慢性模型中，旨在确定与遗传靶向策略无关的结果。特别地，使具有嗜酸性粒细胞发育（Δ dblGATA）和嗜酸性粒细胞募集缺陷的小鼠[CCR 3缺陷的小鼠（CCR 3敲除）和嗜酸性粒细胞活化趋化因子-1和嗜酸性粒细胞活化趋化因子-2两者缺陷的小鼠（嗜酸性粒细胞活化趋化因子-1/2双敲除）]经受烟曲霉诱导的过敏性气道炎症。在eotaxin-1/2双敲除、CCR 3敲除和Delta dbl-GATA小鼠中，变应原诱导的嗜酸性粒细胞向气道的募集分别被消除了98%、94%和99%。重要的是，过敏原诱导的II型辅助性T淋巴细胞细胞因子的产生在嗜酸性粒细胞和CCR 3缺陷小鼠的肺中受损。嗜酸性粒细胞的缺乏与过敏原诱导的粘液产生减少相关。值得注意的是，通过使用全球转录表达谱分析，一个大的子集（29%）的过敏原诱导的基因是嗜酸性粒细胞和CCR 3依赖性的;嗜酸性粒细胞下游的途径被确定，包括在原位激活肺凝血。总之，我们提出了多条独立的证据，表明嗜酸性粒细胞通过CCR 3在慢性过敏性气道疾病中发挥核心作用。
To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (Delta dblGATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1/2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1/2 double knockout, CCR3 knockout, and Delta dbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil- and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil- and CCR3-dependent; pathways downstream from eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.