Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome
Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome
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DOI：
10.1182/blood-2010-03-276972
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发表时间：
2010-10-14
期刊：
影响因子：
20.3
通讯作者：
Huttenlocher, Anna
中科院分区：
文献类型：
--
作者：
Walters, Kevin B.;Green, Julie M.;Huttenlocher, Anna
CXCR4 是一种 G 蛋白偶联趋化因子受体，与原发性免疫缺陷性疾病和癌症的发病机制有关。 CXCR4 的常染色体显性功能获得性截短与疣、低丙种球蛋白血症、感染和骨髓缺乏症 (WHIM) 综合征相关，WHIM 综合征是一种以中性粒细胞减少症和复发性感染为特征的原发性免疫缺陷病。最近的进展表明 CXCR4-SDF1（基质细胞衍生因子 1）信号传导参与调节中性粒细胞稳态，但 CXCR4-SDF1 相互作用在调节体内中性粒细胞运动中的确切作用尚不清楚。在这里，我们利用斑马鱼的光学透明度来可视化 WHIM 综合征斑马鱼模型中中性粒细胞体内的运输。我们证明，斑马鱼中性粒细胞中 WHIM 突变的表达会诱导中性粒细胞滞留在造血组织中，损害中性粒细胞的运动性和伤口募集。 WHIM 截短突变诱导的中性粒细胞滞留信号是 SDF1 依赖性的，因为使用吗啉代寡核苷酸耗尽 SDF1 可恢复中性粒细胞对伤口的趋化性。此外，基因编码的光激活 Rac 鸟苷三磷酸酶的局部激活足以引导表达 WHIM 突变的中性粒细胞迁移。研究结果表明，这种 WHIM 综合征转基因斑马鱼模型可能为筛选修饰 CXCR4-SDF1 保留信号的药物提供有价值的工具。 (血液.2010;116(15):2803-2811)
CXCR4 is a G protein-coupled chemokine receptor that has been implicated in the pathogenesis of primary immunodeficiency disorders and cancer. Autosomal dominant gain-of-function truncations of CXCR4 are associated with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a primary immunodeficiency disorder characterized by neutropenia and recurrent infections. Recent progress has implicated CXCR4-SDF1 (stromal cell-derived factor 1) signaling in regulating neutrophil homeostasis, but the precise role of CXCR4-SDF1 interactions in regulating neutrophil motility in vivo is not known. Here, we use the optical transparency of zebrafish to visualize neutrophil trafficking in vivo in a zebrafish model of WHIM syndrome. We demonstrate that expression of WHIM mutations in zebrafish neutrophils induces neutrophil retention in hematopoietic tissue, impairing neutrophil motility and wound recruitment. The neutrophil retention signal induced by WHIM truncation mutations is SDF1 dependent, because depletion of SDF1 with the use of morpholino oligonucleotides restores neutrophil chemotaxis to wounds. Moreover, localized activation of a genetically encoded, photoactivatable Rac guanosine triphosphatase is sufficient to direct migration of neutrophils that express the WHIM mutation. The findings suggest that this transgenic zebrafish model of WHIM syndrome may provide a valuable tool to screen for agents that modify CXCR4-SDF1 retention signals. (Blood.2010;116(15):2803-2811)