Skip to main content

Advertisement

SpringerLink
Log in

Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Rare monogenic dementias have repeatedly exposed novel pathways guiding to details of the molecular pathogenesis behind this complex clinical phenotype. In this paper, we have studied polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), an early onset dementia with bone fractures caused by mutations in TYROBP (DAP12) and TREM2 genes, which encode important signaling molecules in human dendritic cells (DCs). To identify the pathways and biological processes associated with DAP12/TREM2-mediated signaling, we performed genome wide transcript analysis of in vitro differentiated DCs of PLOSL patients representing functional knockouts of either DAP12 or TREM2. Both DAP12- and TREM2-deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences compared to control cells due to defects in the actin filaments. Not unexpectedly, transcript profiles of the patient DCs showed differential expression of genes involved in immune response. Importantly, significantly diverging transcript levels were also evident for genes earlier associated with other disorders of the central nervous system (CNS) and genes involved in the remodeling of bone, linking these two immunological genes with critical tissue phenotypes of patients. The data underline the functional diversity of the molecules of the innate immune system and implies their significant contribution also in demyelinating CNS disorders, including those resulting in dementia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Hakola HP (1972) Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. Acta Psychiatr Scand Suppl 232:1

    PubMed  CAS  Google Scholar 

  2. Nasu T, Tsukahara Y, Terayama K (1973) A lipid metabolic disease-“membranous lipodystrophy”-an autopsy case demonstrating numerous peculiar membrane-structures composed of compound lipid in bone and bone marrow and various adipose tissues. Acta Pathol Jpn 23:539

    PubMed  CAS  Google Scholar 

  3. Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T, Peltonen L (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25:357

    Article  PubMed  CAS  Google Scholar 

  4. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656

    Article  PubMed  CAS  Google Scholar 

  5. Klunemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502

    Article  PubMed  CAS  Google Scholar 

  6. Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH (1998) Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391:703

    Article  PubMed  CAS  Google Scholar 

  7. McVicar DW, Taylor LS, Gosselin P, Willette-Brown J, Mikhael AI, Geahlen RL, Nakamura MC, Linnemeyer P, Seaman WE, Anderson SK, Ortaldo JR, Mason LH (1998) DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase. J Biol Chem 273:32934

    Article  PubMed  CAS  Google Scholar 

  8. Bouchon A, Hernandez-Munain C, Cella M, Colonna M (2001) A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194:1111

    Article  PubMed  CAS  Google Scholar 

  9. Campbell KS, Colonna M (1999) DAP12: a key accessory protein for relaying signals by natural killer cell receptors. Int J Biochem Cell Biol 31:631

    Article  PubMed  CAS  Google Scholar 

  10. Bouchon A, Dietrich J, Colonna M (2000) Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164:4991

    PubMed  CAS  Google Scholar 

  11. Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M (2003) Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med 198:645

    Article  PubMed  CAS  Google Scholar 

  12. Kiialainen A, Hovanes K, Paloneva J, Kopra O, Peltonen L (2005) Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS. Neurobiol Dis 18:314

    Article  PubMed  CAS  Google Scholar 

  13. Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, Haltia M, Konttinen YT, Peltonen L (2003) DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features. J Exp Med 198:669

    Article  PubMed  CAS  Google Scholar 

  14. Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, Sutcliffe JG, Carson MJ (2002) Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem 83:1309

    Article  PubMed  CAS  Google Scholar 

  15. Veckman V, Miettinen M, Pirhonen J, Siren J, Matikainen S, Julkunen I (2004) Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells. J Leukoc Biol 75:764

    Article  PubMed  CAS  Google Scholar 

  16. Zhang B, Schmoyer D, Kirov S, Snoddy J (2004) GOTree Machine (GOTM): a web-based platform for interpreting sets of interesting genes using Gene Ontology hierarchies. BMC Bioinformatics 5:16

    Article  PubMed  Google Scholar 

  17. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The gene ontology consortium. Nat Genet 25:25

    Article  PubMed  CAS  Google Scholar 

  18. Birney E, Andrews TD, Bevan P, Caccamo M, Chen Y, Clarke L, Coates G, Cuff J, Curwen V, Cutts T, Down T, Eyras E, Fernandez-Suarez XM, Gane P, Gibbins B, Gilbert J, Hammond M, Hotz HR, Iyer V, Jekosch K, Kahari A, Kasprzyk A, Keefe D, Keenan S, Lehvaslaiho H, McVicker G, Melsopp C, Meidl P, Mongin E, Pettett R, Potter S, Proctor G, Rae M, Searle S, Slater G, Smedley D, Smith J, Spooner W, Stabenau A, Stalker J, Storey R, Ureta-Vidal A, Woodwark KC, Cameron G, Durbin R, Cox A, Hubbard T, Clamp M (2004) An overview of Ensembl. Genome Res 14:925

    Article  PubMed  CAS  Google Scholar 

  19. Breitling R, Amtmann A, Herzyk P (2004) Iterative Group Analysis (iGA): a simple tool to enhance sensitivity and facilitate interpretation of microarray experiments. BMC Bioinformatics 5:34

    Article  PubMed  Google Scholar 

  20. Cella M, Sallusto F, Lanzavecchia A (1997) Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol 9:10

    Article  PubMed  CAS  Google Scholar 

  21. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201:647

    Article  PubMed  CAS  Google Scholar 

  22. Kyono WT, de Jong R, Park RK, Liu Y, Heisterkamp N, Groffen J, Durden DL (1998) Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI). J Immunol 161:5555

    PubMed  CAS  Google Scholar 

  23. Lanier LL, Bakker AB (2000) The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunol Today 21:611

    Article  PubMed  CAS  Google Scholar 

  24. Al-Alwan MM, Rowden G, Lee TD, West KA (2001) Fascin is involved in the antigen presentation activity of mature dendritic cells. J Immunol 166:338

    PubMed  CAS  Google Scholar 

  25. Terme M, Tomasello E, Maruyama K, Crepineau F, Chaput N, Flament C, Marolleau JP, Angevin E, Wagner EF, Salomon B, Lemonnier FA, Wakasugi H, Colonna M, Vivier E, Zitvogel L (2004) IL-4 confers NK stimulatory capacity to murine dendritic cells: a signaling pathway involving KARAP/DAP12-triggering receptor expressed on myeloid cell 2 molecules. J Immunol 172:5957

    PubMed  CAS  Google Scholar 

  26. Hamerman JA, Tchao NK, Lowell CA, Lanier LL (2005) Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 6:579

    Article  PubMed  CAS  Google Scholar 

  27. Turnbull IR, McDunn JE, Takai T, Townsend RR, Cobb JP, Colonna M (2005) DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J Exp Med 202:363

    Article  PubMed  CAS  Google Scholar 

  28. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499

    Article  PubMed  CAS  Google Scholar 

  29. Wulczyn FG, Naumann M, Scheidereit C (1992) Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B. Nature 358:597

    Article  PubMed  CAS  Google Scholar 

  30. Hoffmann A, Levchenko A, Scott ML, Baltimore D (2002) The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 298:1241

    Article  PubMed  CAS  Google Scholar 

  31. Aitken CJ, Hodge JM, Nicholson GC (2004) Adenoviral down-regulation of osteopontin inhibits human osteoclast differentiation in vitro. J Cell Biochem 93:896

    Article  PubMed  CAS  Google Scholar 

  32. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294:1731

    Article  PubMed  CAS  Google Scholar 

  33. Bakker AB, Hoek RM, Cerwenka A, Blom B, Lucian L, McNeil T, Murray R, Phillips LH, Sedgwick JD, Lanier LL (2000) DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13:345

    Article  PubMed  CAS  Google Scholar 

  34. Ishizuka K, Kimura T, Igata-yi R, Katsuragi S, Takamatsu J, Miyakawa T 1997) Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin Neurosci 51:135

    Article  PubMed  CAS  Google Scholar 

  35. Kelder W, McArthur JC, Nance-Sproson T, McClernon D, Griffin DE (1998) Beta-chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia. Ann Neurol 44:831

    Article  PubMed  CAS  Google Scholar 

  36. Wilms H, Sievers J, Dengler R, Bufler J, Deuschl G, Lucius R (2003) Intrathecal synthesis of monocyte chemoattractant protein-1 (MCP-1) in amyotrophic lateral sclerosis: further evidence for microglial activation in neurodegeneration. J Neuroimmunol 144:139

    Article  PubMed  CAS  Google Scholar 

  37. Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN (1998) Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions. J Neuroimmunol 84:238

    Article  PubMed  CAS  Google Scholar 

  38. Huang D, Wujek J, Kidd G, He TT, Cardona A, Sasse ME, Stein EJ, Kish J, Tani M, Charo IF, Proudfoot AE, Rollins BJ, Handel T, Ransohoff RM (2005) Chronic expression of monocyte chemoattractant protein-1 in the central nervous system causes delayed encephalopathy and impaired microglial function in mice. FASEB J 19:761

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Janna Saarela for the help with the microarray analysis, Henna Linturi for the help with the RT-PCR analysis, Sampo Sammalisto for the help with the statistical analysis, and Taina Kytömaa for critical reading of the manuscript. Päivi Tainola and Lea Puhakka are thanked for technical assistance. This study was supported by the Helsinki Graduate School in Biotechnology and Molecular Biology (A.K. and V.V.), the MicMan Programme, the Center of Excellence in Disease Genetics of the Finnish Academy, the Biocentrum Helsinki, the NIH grant NS 43559, and the Neuropromise EU project LSHM-CT-2005-018637. The authors have no conflicting financial interests.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, National Public Health Institute, Biomedicum, Haartmaninkatu 8, 00290, Helsinki, Finland

    Anna Kiialainen, Juha Saharinen, Juha Paloneva, Outi Kopra & Leena Peltonen

  2. Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland

    Ville Veckman & Ilkka Julkunen

  3. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Leena Peltonen

  4. Biomedicum Bioinformatics Unit, University of Helsinki, Helsinki, Finland

    Juha Saharinen & Massimiliano Gentile

  5. Department of Forensic Psychiatry, University of Kuopio, Kuopio, Finland

    Panu Hakola

  6. Department of Neurology, Ghent University Hospital, Ghent, Belgium

    Dimitri Hemelsoet

  7. Dementia Research Centre, National Hospital for Neurology and Neurosurgery, London, UK

    Basil Ridha

  8. Neuroscience Center, University of Helsinki, Helsinki, Finland

    Outi Kopra

  9. The Broad Institute, MIT, Boston, MA, USA

    Leena Peltonen

Authors
  1. Anna Kiialainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ville Veckman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juha Saharinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juha Paloneva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Massimiliano Gentile
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Panu Hakola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dimitri Hemelsoet
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Basil Ridha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Outi Kopra
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ilkka Julkunen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Leena Peltonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leena Peltonen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kiialainen, A., Veckman, V., Saharinen, J. et al. Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response. J Mol Med 85, 971–983 (2007). https://doi.org/10.1007/s00109-007-0191-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-007-0191-4

Keywords

Search

Navigation