TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors
TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors
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DOI：
10.1016/j.bbi.2011.03.006
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发表时间：
2011-08-01
影响因子：
15.1
通讯作者：
Drexhage, Hemmo A.
中科院分区：
文献类型：
--
作者：
Weigelt, Karin;Carvalho, Livia A.;Drexhage, Hemmo A.
免疫激活是精神分裂症（SCZ）、双相情感障碍（BD）和单相抑郁症（MDD）的特征。髓样细胞表达触发受体1（TREM-1）及其衔接分子DAP 12和转录因子（TF）PU.1是炎症反应的重要关键基因，在活化的单核细胞和小胶质细胞中表达。（1）如果TREM-1的表达式，DAP 12和PU. 1在患有严重精神障碍的患者的单核细胞中增加，以及（2）如果PU. 1和TF、ATF 3和EGFR 3（在先前的研究中发现其为显著增加的单核细胞基因）参与TREM-1和DAP 12表达的调节。采用定量PCR方法检测了73例严重精神疾病患者单核细胞TREM-1、DAP 12、PU.1、ATF 3和EGFR 3基因的表达（27名新近发作的SCZ患者，22名BD患者和24名MDD患者）和79名健康对照（HC）。采用计算机模拟TF结合位点预测和体内染色质免疫沉淀（ChIP）技术，研究了EGFR 3、ATF 3和PU. 1与TREM-1和DAP 12启动子区的实际结合。TREM-1基因在SCZ和BD患者单核细胞中表达增加，在MDD患者单核细胞中有增加的趋势.在SCZ、BD和MDD患者的单核细胞中，DAP 12基因水平均未升高. MDD患者单核细胞PU.1表达水平升高，而SCZ和BD患者单核细胞PU.1表达水平无明显变化. TREM-1表达水平特别与ATF 3和EGR 3表达水平相关，DAP 12表达水平特别与PU.1表达水平相关。我们发现，使用结合位点预测和ChIP分析，TF EGR 3和ATF 3确实结合到TREM-1启动子，PU.1结合到TREM-1和DAP 12 promoter.Conclusion：在这项研究中，我们提供的证据表明，TREM-1基因表达显着增加SCZ和BD患者的单核细胞和TREM-1基因是TF ATF 3和EGR 3的靶基因。在MDD患者中，PU.1基因表达增加，有TREM-1基因过度表达的趋势。我们的观察结果支持单核细胞在严重精神疾病中处于促炎状态的概念，并表明SCZ之间单核细胞炎症设定点的差异。BD和MDD。(C)2011 Elsevier Inc. All rights reserved.
Introduction: Immune activation is a characteristic of schizophrenia (SCZ), bipolar disorder (BD) and unipolar major depressive disorder (MDD). The triggering receptor expressed on myeloid cells 1 (TREM-1), its' adaptor molecule DAP12 and their transcription factor (TF) PU.1 are important key genes in inflammation and expressed in activated monocytes and microglia.Aim: To test: (1) if the expressions of TREM-1, DAP12 and PU.1 are increased in monocytes of patients with severe psychiatric disorders and (2) if PU.1 and the TFs ATF3 and EGR3 (which have been found as prominent increased monocyte genes in previous studies) are involved in the regulation of TREM-1 and DAP12 expression.Methods: Using Q-PCR, we studied the gene expression of TREM-1, DAP12, PU.1, ATF3 and EGR3 in the monocytes of 73 patients with severe psychiatric disorders (27 recent onset SCZ patients, 22 BD patients and 24 MDD patients) and of 79 healthy controls (HC). Using in silico TF binding site prediction and in vivo chromatin immunoprecipitation (ChIP), we studied the actual binding of EGR3, ATF3 and PU.1 to the promoter regions of TREM-1 and DAP12.Results:1. TREM-1 gene expression was increased in the monocytes of SCZ and BD patients and tended to be increased in the monocytes of MDD patients.2. DAP12 gene levels were neither increased in the monocytes of SCZ, BD, nor MDD patients.3. PU.1 expression levels were increased in the monocytes of MDD patients, but not in those of SCZ and BD patients.4. TREM-1 expression levels correlated in particular to ATF3 and EGR3 expression levels, DAP12 expression levels correlated in particular to PU.1 expression levels.5. We found using binding site prediction and ChIP assays that the TFs EGR3 and ATF3 indeed bound to the TREM-1 promoter, PU.1 bound to both the TREM-1 and DAP12 promoter.Conclusion: In this study, we provide evidence that TREM-1 gene expression is significantly increased in monocytes of SCZ and BD patients and that the TREM-1 gene is a target gene of the TFs ATF3 and EGR3. In MDD patients, PU.1 gene expression was increased with a tendency for TREM-1 gene over expression. Our observations support the concept that monocytes are in a pro-inflammatory state in severe psychiatric conditions and suggest differences in monocyte inflammatory set points between SCZ. BD and MDD. (C) 2011 Elsevier Inc. All rights reserved.