Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis
Irf8 regulates macrophage versus neutrophil fate during zebrafish primitive myelopoiesis
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DOI：
10.1182/blood-2010-06-290700
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发表时间：
2011-01-27
期刊：
影响因子：
20.3
通讯作者：
Wen, Zilong
中科院分区：
文献类型：
--
作者：
Li, Li;Jin, Hao;Wen, Zilong
在脊椎动物中，骨髓细胞包含多形核和单核谱系，这些谱系由两个连续的发育波产生：在胚胎阶段产生有限的骨髓细胞的短暂原始波和能够在整个胎儿和成年生命中产生骨髓细胞的决定波。一个尚未解决的关键问题是，哪些因素决定了骨髓生成过程中多形核与单核谱系的命运。在这里，我们发现在斑马鱼胚胎发生过程中，干扰素调节因子 8 (irf8) 在巨噬细胞中特异性表达，但在中性粒细胞中不表达。抑制斑马鱼中的 Irf8 功能会导致巨噬细胞耗竭和中性粒细胞输出增加，但不会影响原始骨髓细胞的总数、增殖和存活。这些数据表明，Irf8 敲低胚胎中骨髓谱系发育的倾斜是细胞命运转换的结果。这一结论得到了以下观察结果的进一步支持：Irf8 的过度表达会促进巨噬细胞的形成，但会损害中性粒细胞的发育。遗传上位分析表明，Irf8 作用于 Pu.1 下游，但在 Pu.1 缺失的情况下不足以促进巨噬细胞发育。我们的研究结果表明，Irf8 是斑马鱼原始骨髓生成过程中中性粒细胞与巨噬细胞命运选择的关键决定因素。 （血。2011；117（4）：1359-1369）
In vertebrates, myeloid cells comprise polymorphonuclear and mononuclear lineages that arise from 2 successive waves of development: a transitory primitive wave giving rise to limited myeloid cells during embryonic stage and a definitive wave capable of producing myeloid cells throughout the fetal and adult life. One key unresolved question is what factors dictate polymorphonuclear versus mononuclear lineage fates during myelopoiesis. Here we show that during zebrafish embryogenesis interferon regulatory factor-8 (irf8) is expressed specifically in macrophages but not neutrophils. Suppression of Irf8 function in zebrafish causes a depletion of macrophages and an enhanced output of neutrophils but does not affect the overall number, proliferation, and survival of primitive myeloid cells. These data indicate that the skewed myeloid lineage development in Irf8 knockdown embryos results from a cell-fate switching. Such a conclusion is further supported by the observation showing that overexpression of Irf8 promotes macrophage formation at the expense of neutrophil development. Genetic epistasis analysis reveals that Irf8 acts downstream of Pu.1 but is insufficient to promote macrophage development in the absence of Pu.1. Our findings demonstrate that Irf8 is a critical determinant for neutrophil versus macrophage fate choice during zebrafish primitive myelopoiesis. (Blood. 2011; 117(4):1359-1369)