GATA-1 regulates the generation and function of basophils
GATA-1 regulates the generation and function of basophils
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DOI：
10.1073/pnas.1311668110
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发表时间：
2013-11-12
影响因子：
11.1
通讯作者：
Karasuyama, Hajime
中科院分区：
文献类型：
--
作者：
Nei, Yuichiro;Obata-Ninomiya, Kazushige;Karasuyama, Hajime
造血细胞的发育过程是由转录网络协调的。加塔-1是加塔家族转录因子的创始成员，已被证明在红系细胞、巨核细胞、嗜酸性粒细胞和肥大细胞的分化中起关键作用。然而，加塔-1在嗜碱性粒细胞中的作用仍然难以捉摸。在这里，我们表明，嗜碱性粒细胞丰富地表达Gata 1 mRNA，和siRNA介导的Gata 1敲低导致嗜碱性粒细胞响应于IgE加抗原刺激的IL-4产生受损。Delta dblGATA小鼠携带突变的Gata 1启动子，由于其嗜酸性粒细胞的选择性损失而被广泛用于嗜酸性粒细胞的功能分析，其显示嗜碱性粒细胞数量减少，Gata 1 mRNA表达减少。在这些小鼠中，骨髓中嗜碱性祖细胞的数量减少，与IL-3或胸腺基质淋巴细胞生成素一起培养的骨髓细胞中嗜碱性粒细胞的生成受损。如通过脱粒和IL-4和IL-6的产生所评估的，与野生型嗜碱性粒细胞相比，Δ dblGATA嗜碱性粒细胞对IgE加抗原的刺激的离体反应较差。此外，Delta dblGATA小鼠在嗜碱性粒细胞介导的针对肠道蠕虫感染的保护性免疫中表现出受损的应答。因此，除了已知的嗜酸性粒细胞缺乏外，Delta dblGATA小鼠还显示出嗜碱性粒细胞的数量和功能异常。我们的研究结果表明，加塔-1在嗜碱性粒细胞的产生和功能中起着关键作用，并强调需要仔细区分负责在Delta dbl加塔小鼠中观察到的每种表型的细胞谱系。
Developmental processes of hematopoietic cells are orchestrated by transcriptional networks. GATA-1, the founding member of the GATA family of transcription factors, has been demonstrated to play crucial roles in the differentiation of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remains elusive. Here we show that basophils abundantly express Gata1 mRNAs, and that siRNA-mediated knockdown of Gata1 resulted in impaired production of IL-4 by basophils in response to the stimulation with IgE plus antigens. Delta dblGATA mice that carry the mutated Gata1 promoter and are widely used for functional analysis of eosinophils owing to their selective loss of eosinophils showed a decreased number of basophils with reduced expression of Gata1 mRNAs. The number of basophil progenitors in bone marrow was reduced in these mice, and the generation of basophils from their bone marrow cells in culture with IL-3 or thymic stromal lymphopoietin was impaired. Delta dblGATA basophils responded poorly ex vivo to stimulation with IgE plus antigens compared with wild-type basophils as assessed by degranulation and production of IL-4 and IL-6. Moreover, Delta dblGATA mice showed impaired responses in basophil-mediated protective immunity against intestinal helminth infection. Thus, Delta dblGATA mice showed numerical and functional aberrancy in basophils in addition to the known deficiency of eosinophils. Our findings demonstrate that GATA-1 plays a key role in the generation and function of basophils and underscore the need for careful distinction of the cell lineage responsible for each phenotype observed in Delta dblGATA mice.