State Key Laboratory of Molecular Neuroscience, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China.
Blood. 2011 Jan 27;117(4):1359-69. doi: 10.1182/blood-2010-06-290700. Epub 2010 Nov 15.
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.
在脊椎动物中，髓系细胞包括多形核细胞和单核细胞谱系，它们来自于 2 个连续的发育波：一个短暂的原始波在胚胎期产生有限的髓系细胞，一个确定的波能够在胎儿期和成年期产生髓系细胞。一个尚未解决的关键问题是，在髓样细胞生成过程中，是什么因素决定了多形核细胞与单核细胞谱系的命运。在这里，我们表明，在斑马鱼胚胎发生过程中，干扰素调节因子-8（irf8）特异性地在巨噬细胞中表达，但不在中性粒细胞中表达。在斑马鱼中抑制 Irf8 的功能会导致巨噬细胞耗竭和中性粒细胞产量增加，但不影响原始髓系细胞的总数、增殖和存活。这些数据表明，irf8 敲低胚胎中偏向的髓系谱系发育是由于细胞命运转换。这一结论进一步得到了以下观察结果的支持：过表达 Irf8 以牺牲中性粒细胞发育为代价促进巨噬细胞形成。遗传上位性分析表明，Irf8 作用于 Pu.1 下游，但在没有 Pu.1 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 是斑马鱼原始髓样细胞生成中决定中性粒细胞与巨噬细胞命运选择的关键决定因素。
