Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency
Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency
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DOI：
10.1189/jlb.0504286
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发表时间：
2005-11-01
影响因子：
5.5
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Gombart, AF;Krug, U;Koeffler, HP
嗜中性粒细胞缺乏症涉及CCAAT/增强子结合蛋白epsilon(C/EBPE)基因的种系突变。缺乏活性C/EBPF的人类和小鼠由于功能缺陷的中性粒细胞和巨噬细胞而频繁遭受细菌感染。我们假设这些缺陷反映了重要免疫反应基因的失调。为了验证这一点，用DNA芯片检测了C/EBP epsilon-/-和野生型小鼠腹膜来源的中性粒细胞和巨噬细胞的基因表达差异。在283个基因中，146个已知基因和21个表达序列标签(EST)在C/EBP-/-小鼠中下调，85个已知基因和31个EST上调。这些基因包括与细胞黏附/趋化、细胞骨架组织、信号转导和免疫/炎症反应有关的基因。细胞因子CC趋化因子配体4、CXC趋化因子、配体2、白介素6以及细胞因子受体IL-8Rb、粒细胞集落刺激因子表达下调。染色质免疫沉淀分析证实C/EBPF与其启动子区域结合。脂代谢基因载脂蛋白E(APOE)、清道夫受体B-1、包含低密度脂蛋白受体A类重复1的分类蛋白相关受体1和APOC2在C/EBP epsilon-/小鼠中的表达增加与这些小鼠在高脂饮食维持前后总胆固醇水平的降低相关。此外，缺乏C/EBP epsilon的巨噬细胞积累脂质的能力降低。总之，许多新的C/EBPF靶基因的失调会损害先天免疫反应，并可能损害由中性粒细胞和巨噬细胞介导的其他重要生物学过程。
Nentrophil-specific granule deficiency involves inheritance of germline mutations in the CCAAT/enhancer-binding protein epsilon (C/EBPE) gene. Humans and mice lacking active C/EBPF suffer frequent bacterial infections as a result of functionally defective neutrophils and macrophages. We hypothesized that these defects reflected dysregulation of important immune response genes. To test this, gene expression differences of peritoneally derived nentrophils and macrophages from C/EBP epsilon-/- and wild-type mice were determined with DNA microarrays. Of 283 genes, 146 known genes and 21 expressed sequence tags (ESTs) were down-regulated, and 85 known genes and 31 ESTs were up-regulated in the C/EBP-/- mice. These included genes involved in cell adhesion/chemotaxis, cytoskeletal organization, signal transduction, and immune/inflammatory responses. The cytokines CC chemokine ligand 4, CXC chemokine,ligand 2, and interleukin (IL)-6, as well as cytokine receptors IL-8RB and granulocyte-colony stimulating factor, were down-regulated. Chromatin immunoprecipitation analysis identified binding of C/EBPF to their promoter regions. Increased expression for lipid metabolism genes apolipoprotein E (APOE), scavenger receptor class B-1, sorting protein-related receptor containing low-density lipoprotein receptor class A repeat 1, and APOC2 in the C/EBP epsilon-/mice correlated with reduced total cholesterol levels in these mice before and after maintenance on a high-fat diet. Also, C/EBP epsilon-deficient macrophages showed a reduced capacity to accumulate lipids. In summary, dysregulation of numerous, novel C/EBPF target genes impairs innate immune response and possibly other important biological processes mediated by neutrophils and macrophages.