Skip to main content

Advertisement

SpringerLink
Log in

CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Recent studies demonstrated that primary immune responses can be induced within the brain depending on vessel-associated cells expressing markers of dendritic cells (DC). Using mice transcribing the green fluorescent protein (GFP) under the promoter of the DC marker CD11c, we determined the distribution, phenotype, and source of CD11c+ cells in non-diseased brains. Predilection areas of multiple sclerosis (MS) lesions (periventricular area, adjacent fibre tracts, and optical nerve) were preferentially populated by CD11c+ cells. Most CD11c+ cells were located within the juxtavascular parenchyma rather than the perivascular spaces. Virtually all CD11c+ cells co-expressed ionized calcium-binding adaptor molecule 1 (IBA-1), CD11b, while detectable levels of major histocompatibility complex II (MHC-II) in non-diseased mice was restricted to CD11c+ cells of the choroid plexus. Cellular processes project into the glia limitans which may allow transport and/or presentation of intraparenchymal antigens to extravasated T cells in perivascular spaces. In chimeric mice bearing CD11c-GFP bone marrow, fluorescent cells appeared in the CNS between 8 and 12 weeks after transplantation. In organotypic slice cultures from CD11c-GFP mice, the number of fluorescent cells strongly increased within 72 h. Strikingly, using anti-CD209, an established marker for human DC, a similar population was detected in human brains. Thus, we show for the first time that CD11c+ cells can not only be recruited from the blood into the parenchyma, but also develop from an intraneural precursor in situ. Dysbalance in their recruitment/development may be an initial step in the pathogenesis of chronic (autoimmune) neuroinflammatory diseases such as MS.

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
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Agrawal S, Anderson P, Durbeej M et al (2006) Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 203:1007–1019

    Article  PubMed  CAS  Google Scholar 

  2. Babcock AA, Kuziel WA, Rivest S, Owens T (2003) Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 23:7922–7930

    PubMed  CAS  Google Scholar 

  3. Bechmann I (2005) Failed central nervous system regeneration: a downside of immune privilege? Neuromolecular Med 7:217–228

    Article  PubMed  CAS  Google Scholar 

  4. Bechmann I, Galea I, Perry VH (2007) What is the blood–brain barrier (not)? Trends Immunol 28:5–11

    Article  PubMed  CAS  Google Scholar 

  5. Bechmann I, Goldmann J, Kovac AD et al (2005) Circulating monocytic cells infiltrate layers of anterograde axonal degeneration where they transform into microglia. FASEB J 19:647–649

    PubMed  CAS  Google Scholar 

  6. Bechmann I, Nitsch R (1997) Astrocytes and microglial cells incorporate degenerating fibers following entorhinal lesion: a light, confocal, and electron microscopical study using a phagocytosis-dependent labeling technique. Glia 20:145–154

    Article  PubMed  CAS  Google Scholar 

  7. Bechmann I, Peter S, Beyer M, Gimsa U, Nitsch R (2001) Presence of B7–2 (CD86) and lack of B7–1 (CD(80) on myelin phagocytosing MHC-II-positive rat microglia is associated with nondestructive immunity in vivo. FASEB J 15:1086–1088

    PubMed  CAS  Google Scholar 

  8. Billingham RE, Boswell T (1953) Studies on the problem of corneal homografts. Proc R Soc Lond B Biol Sci 141:392–406

    Article  PubMed  CAS  Google Scholar 

  9. Carson MJ, Reilly CR, Sutcliffe JG, Lo D (1999) Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. Am J Pathol 154:481–494

    Article  PubMed  CAS  Google Scholar 

  10. Cserr HF, Knopf PM (1992) Cervical lymphatics, the blood–brain barrier and the immunoreactivity of the brain: a new view. Immunol Today 13:507–512

    Article  PubMed  CAS  Google Scholar 

  11. de Vos AF, van Meurs M, Brok HP et al (2002) Transfer of central nervous system autoantigens and presentation in secondary lymphoid organs. J Immunol 169:5415–5423

    PubMed  Google Scholar 

  12. Fabriek BO, Zwemmer JN, Teunissen CE et al (2005) In vivo detection of myelin proteins in cervical lymph nodes of MS patients using ultrasound-guided fine-needle aspiration cytology. J Neuroimmunol 161:190–194

    Article  PubMed  CAS  Google Scholar 

  13. Fischer HG, Reichmann G (2001) Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 166:2717–2726

    PubMed  CAS  Google Scholar 

  14. Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18

    Article  PubMed  CAS  Google Scholar 

  15. Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I (2006) T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol 80:797–801

    Article  PubMed  CAS  Google Scholar 

  16. Greter M, Heppner FL, Lemos MP et al (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328–334

    Article  PubMed  CAS  Google Scholar 

  17. Hatterer E, Davoust N, Didier-Bazes M et al (2006) How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 107:806–812

    Article  PubMed  CAS  Google Scholar 

  18. Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292

    Article  PubMed  CAS  Google Scholar 

  19. Jung S, Unutmaz D, Wong P et al (2002) In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17:211–220

    Article  PubMed  CAS  Google Scholar 

  20. Kansas GS, Muirhead MJ, Dailey MO (1990) Expression of the CD11/CD18, leukocyte adhesion molecule 1, and CD44 adhesion molecules during normal myeloid and erythroid differentiation in humans. Blood 76:2483–2492

    PubMed  CAS  Google Scholar 

  21. Karman J, Chu HH, Co DO, Seroogy CM, Sandor M, Fabry Z (2006) Dendritic cells amplify T cell-mediated immune responses in the central nervous system. J Immunol 177:7750–7760

    PubMed  CAS  Google Scholar 

  22. Keizer GD, Borst J, Visser W, Schwarting R, de Vries JE, Figdor CG (1987) Membrane glycoprotein p150, 95 of human cytotoxic T cell clone is involved in conjugate formation with target cells. J Immunol 138:3130–3136

    PubMed  CAS  Google Scholar 

  23. Kishimoto TK, Larson RS, Corbi AL, Dustin ML, Staunton DE, Springer TA (1989) The leukocyte integrins. Adv Immunol 46:149–182

    Article  PubMed  CAS  Google Scholar 

  24. Kluge A, Hailer NP, Horvath TL, Bechmann I, Nitsch R (1998) Tracing of the entorhinal-hippocampal pathway in vitro. Hippocampus 8:57–68

    Article  PubMed  CAS  Google Scholar 

  25. Kovac AD, Kwidzinski E, Heimrich BI et al (2004) Entorhinal cortex lesion in the mouse induces transsynaptic death of perforant path target neurons. Brain Pathol 14:249–257

    Article  PubMed  Google Scholar 

  26. Ladeby R, Wirenfeldt M, Dalmau I et al (2005) Proliferating resident microglia express the stem cell antigen CD34 in response to acute neural injury. Glia 50:121–131

    Article  PubMed  Google Scholar 

  27. Larson RS, Springer TA (1990) Structure and function of leukocyte integrins. Immunol Rev 114:181–217

    Article  PubMed  CAS  Google Scholar 

  28. Lassmann H, Zimprich F, Vass K, Hickey WF (1991) Microglial cells are a component of the perivascular glia limitans. J Neurosci Res 28(2):236–243

    Article  PubMed  CAS  Google Scholar 

  29. Lopez-Cabrera M, Nueda A, Vara A, Garcia-Aguilar J, Tugores A, Corbi AL (1993) Characterization of the p150, 95 leukocyte integrin alpha subunit (CD11c) gene promoter. Identification of cis-acting elements. J Biol Chem 268:1187–1193

    PubMed  CAS  Google Scholar 

  30. Matyszak MK, Perry VH (1996) The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 74:599–608

    Article  PubMed  CAS  Google Scholar 

  31. Matyszak MK, Perry VH (1998) Bacillus Calmette-Guerin sequestered in the brain parenchyma escapes immune recognition. J Neuroimmunol 82:73–80

    Article  PubMed  CAS  Google Scholar 

  32. McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD (2005) Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11:335–339

    Article  PubMed  CAS  Google Scholar 

  33. McMenamin PG (1999) Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 405:553–562

    Article  PubMed  CAS  Google Scholar 

  34. McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B (2003) Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res 313:259–269

    Article  PubMed  Google Scholar 

  35. Medawar PB (1948) Immunity to homologous grafted skin. III. The fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 29:58–69

    PubMed  CAS  Google Scholar 

  36. Mildner A, Schmidt H, Nitsche M et al (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10(12):1544–1553

    Article  PubMed  CAS  Google Scholar 

  37. Mutlu L, Brandt C, Kwidzinski E et al (2007) Tolerogenic effect of fiber tract injury: reduced EAE severity following entorhinal cortex lesion. Exp Brain Res 178:542–553

    Article  PubMed  Google Scholar 

  38. Myones BL, Dalzell JG, Hogg N, Ross GD (1988) Neutrophil and monocyte cell surface p150, 95 has iC3b-receptor (CR4) activity resembling CR3. J Clin Invest 82:640–651

    Article  PubMed  CAS  Google Scholar 

  39. Newman TA, Galea I, van Rooijen N, Perry VH (2005) Blood-derived dendritic cells in an acute brain injury. J Neuroimmunol 166:167–172

    Article  PubMed  CAS  Google Scholar 

  40. Owens T, Bechmann I, Engelhardt B (2008) Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol 67:1113–1121

    Article  PubMed  Google Scholar 

  41. Pashenkov M, Huang YM, Kostulas V, Haglund M, Soderstrom M, Link H (2001) Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 124:480–492

    Article  PubMed  CAS  Google Scholar 

  42. Pashenkov M, Teleshova N, Link H (2003) Inflammation in the central nervous system: the role for dendritic cells. Brain Pathol 13:23–33

    Article  PubMed  Google Scholar 

  43. Perry VH (2000) Persistent pathogens in the parenchyma of the brain. J Neurovirol 6(Suppl):86–89

    Google Scholar 

  44. Postigo AA, Corbi AL, Sanchez-Madrid F, de Landazuri MO (1991) Regulated expression and function of CD11c/CD18 integrin on human B lymphocytes. Relation between attachment to fibrinogen and triggering of proliferation through CD11c/CD18. J Exp Med 174:1313–1322

    Article  PubMed  CAS  Google Scholar 

  45. Reboldi A, Coisne C, Baumjohann D et al (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10:514–523

    Article  PubMed  CAS  Google Scholar 

  46. Reichmann G, Schroeter M, Jander S, Fischer HG (2002) Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J Neuroimmunol 129:125–132

    Article  PubMed  CAS  Google Scholar 

  47. Rosicarelli B, Serafini B, Sbriccoli M et al (2005) Migration of dendritic cells into the brain in a mouse model of prion disease. J Neuroimmunol 165:114–120

    Article  PubMed  CAS  Google Scholar 

  48. Sadhu C, Ting HJ, Lipsky B et al (2007) CD11c/CD18: novel ligands and a role in delayed-type hypersensitivity. J Leukoc Biol 81:1395–1403

    Article  PubMed  CAS  Google Scholar 

  49. Santambrogio L, Belyanskaya SL, Fischer FR et al (2001) Developmental plasticity of CNS microglia. Proc Natl Acad Sci USA 98:6295–6300

    Article  PubMed  CAS  Google Scholar 

  50. Schwarting R, Stein H, Wang CY (1985) The monoclonal antibodies alpha S-HCL 1 (alpha Leu-14) and alpha S-HCL 3 (alpha Leu-M5) allow the diagnosis of hairy cell leukemia. Blood 65:974–983

    PubMed  CAS  Google Scholar 

  51. Serafini B, Columba-Cabezas S, Di RF, Aloisi F (2000) Intracerebral recruitment and maturation of dendritic cells in the onset and progression of experimental autoimmune encephalomyelitis. Am J Pathol 157:1991–2002

    Article  PubMed  CAS  Google Scholar 

  52. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F (2004) Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 14:164–174

    Article  PubMed  Google Scholar 

  53. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood–brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153:933–946

    Article  PubMed  CAS  Google Scholar 

  54. Stacker SA, Springer TA (1991) Leukocyte integrin P150, 95 (CD11c/CD18) functions as an adhesion molecule binding to a counter-receptor on stimulated endothelium. J Immunol 146:648–655

    PubMed  CAS  Google Scholar 

  55. Suter T, Biollaz G, Gatto D et al (2003) The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation. Eur J Immunol 33:2998–3006

    Article  PubMed  CAS  Google Scholar 

  56. Te Velde AA, Keizer GD, Figdor CG (1987) Differential function of LFA-1 family molecules (CD11 and CD18) in adhesion of human monocytes to melanoma and endothelial cells. Immunology 61:261–267

    PubMed  CAS  Google Scholar 

  57. Toft-Hansen H, Buist R, Sun XJ, Schellenberg A, Peeling J, Owens T (2006) Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system. J Immunol 177:7242–7249

    PubMed  CAS  Google Scholar 

  58. Tran EH, Hoekstra K, van Roojien N, Dijkstra CD, Owens T (1998) Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol 161:3767–3775

    PubMed  CAS  Google Scholar 

  59. van Zwam M, Huizinga R, Melief MJ et al (2009) Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE. J Mol Med 87:273–286

    Article  PubMed  Google Scholar 

  60. Walther M, Popratiloff A, Lachnit N et al (2001) Exogenous antigen containing perivascular phagocytes induce a non-encephalitogenic extravasation of primed lymphocytes. J Neuroimmunol 117:30–42

    Article  PubMed  CAS  Google Scholar 

  61. Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266

    Article  PubMed  CAS  Google Scholar 

  62. Wirenfeldt M, Babcock AA, Ladeby R et al (2005) Reactive microgliosis engages distinct responses by microglial subpopulations after minor central nervous system injury. J Neurosci Res 82:507–514

    Article  PubMed  CAS  Google Scholar 

  63. Wirenfeldt M, Dissing-Olesen L, Anne BA et al (2007) Population control of resident and immigrant microglia by mitosis and apoptosis. Am J Pathol 171:617–631

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the DFG (FoGr “Fate of barin macrophages” to I.B.), the Dutch MS Research Foundation (JDL) and the COST consortium NEURINFNET (BM0603: J.D.L., B.B., I.B.). The Olympus Fluoview microscope was financed by the Kassel-Stiftung, the Messer-Stiftung, and the Dr. Senckenberg-Stiftung. We gratefully acknowledge the help of these Frankfurt foundations. I.B. is a fellow of the Frankfurt Institute of Advanced Studies (FIAS).

Author information

Authors and Affiliations

  1. Institute of Clinical Neuroanatomy, Johann Wolfgang Goethe-University, 60590, Frankfurt/Main, Germany

    Carolin Prodinger, Martin Krüger, Fridtjof Schiefenhövel & Ingo Bechmann

  2. Institute of Anatomy, University of Leipzig, 04103, Leipzig, Germany

    Jörg Bunse, Martin Krüger, Fridtjof Schiefenhövel, Kerstin Immig & Ingo Bechmann

  3. Institute of Cell and Neurobiology, Charité, 10098, Berlin, Germany

    Jörg Bunse & Christine Brandt

  4. Department of Immunology, MS Centre ErasMS, Erasmus MC, 3000 DR, Rotterdam, The Netherlands

    Jon D. Laman

  5. Neuroimmunology Unit, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland

    Melanie Greter & Burkhard Becher

  6. Institute for Neuropathology, Charité, Berlin, Germany

    Frank Heppner

Authors
  1. Carolin Prodinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jörg Bunse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin Krüger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fridtjof Schiefenhövel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christine Brandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jon D. Laman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Melanie Greter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kerstin Immig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank Heppner
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Burkhard Becher
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ingo Bechmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ingo Bechmann.

Additional information

Carolin Prodinger, Jörg Bunse have contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prodinger, C., Bunse, J., Krüger, M. et al. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 121, 445–458 (2011). https://doi.org/10.1007/s00401-010-0774-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0774-y

Keywords

Search

Navigation