Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways
Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways
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DOI：
10.1371/journal.pone.0108553
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发表时间：
2014-10-03
期刊：
影响因子：
3.7
通讯作者：
Monach, Paul A.
中科院分区：
文献类型：
--
作者：
Ericson, Jeffrey A.;Duffau, Pierre;Monach, Paul A.
作为免疫基因组计划（ImmGen）的一部分，在未受刺激的（循环）小鼠中性粒细胞和体内活化的三个中性粒细胞群体中测定基因表达，并将这些群体与其他白细胞进行比较。活化条件包括血清转移关节炎（由免疫复合物介导）、巯基乙酸盐诱导的腹膜炎和尿酸诱导的腹膜炎。中性粒细胞表达的基因比ImmGen研究的任何其他白细胞群体都少，与翻译相关的基因下调尤其引人注目。然而，还鉴定了对中性粒细胞具有相对特异性表达的基因，特别是三个功能未知的基因：Stfa2l1、Mrgpr2a和Mrgpr2b。比较活化中性粒细胞中上调的基因，得出了几个新的发现：与谷胱甘肽合成和使用相关的基因以及与修饰脂蛋白摄入和代谢相关的基因的表达增加，特别是在硫乙醇酸盐引起的中性粒细胞中; Nr 4a家族中转录因子基因的表达增加，仅在血清转移关节炎引起的中性粒细胞中;以及增加在白藜芦醇合成中重要的基因的表达和对白三烯的应答，特别是在由尿酸引起的嗜中性粒细胞中。与先前的研究一致，还观察到与细胞凋亡、对微生物产物的反应、NFkB家族成员及其调节剂和MHC II类表达相关的基因的上调。从ImmGen数据开发的调控模型用于推断参与中性粒细胞活化过程中基因表达变化的调控基因。在64个预测影响这些基因表达变化的大多数新的调控基因中，Irf5显示出对于在体外通过TLR9刺激后小鼠嗜中性粒细胞最佳分泌IL-10、IP-10、MIP-1 α、MIP-1 β和TNF-α是重要的。该数据集及其使用ImmGen调控模型的分析为关于不同条件下中性粒细胞基因表达变化的重要性的基于假设的研究提供了基础。
As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1 alpha, MIP-1 beta, and TNF-alpha by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions.