title: TREM-1 and DAP12 expression in monocytes of patients with severe psychiatric disorders. EGR3, ATF3 and PU.1 as important transcription factors.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Immunology, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands. k.weigelt@erasmusmc.nl
authors.forename: Karin
authors.initials: K
authors.lastname: Weigelt
authors.forename: Livia A
authors.initials: LA
authors.lastname: Carvalho
authors.forename: Roos C
authors.initials: RC
authors.lastname: Drexhage
authors.forename: Annemarie
authors.initials: A
authors.lastname: Wijkhuijs
authors.forename: Harm
authors.initials: H
authors.lastname: de Wit
authors.forename: Nico J M
authors.initials: NJ
authors.lastname: van Beveren
authors.forename: Tom K
authors.initials: TK
authors.lastname: Birkenhäger
authors.forename: Veerle
authors.initials: V
authors.lastname: Bergink
authors.forename: Hemmo A
authors.initials: HA
authors.lastname: Drexhage
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051776:Early Growth Response Protein 3 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D007297:Inpatients; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D015213:Neuroimmunomodulation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011619:Psychotropic Drugs / Q000494:pharmacology / Q000627:therapeutic use; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D055815:Young Adult; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051700:Activating Transcription Factor 3; D048868:Adaptor Proteins, Signal Transducing; D051776:Early Growth Response Protein 3; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011619:Psychotropic Drugs; D011971:Receptors, Immunologic; D015534:Trans-Activators; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D000099232:Proto-Oncogene Protein Spi-1; C490449:ATF3 protein, human; C079945:EGR3 protein, human; C408842:TREM1 protein, human; C110546:TYROBP protein, human