Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions

Nature Neuroscience volume 10, pages 1544–1553 (2007)Cite this article

Abstract

Microglia are crucially important myeloid cells in the CNS and constitute the first immunological barrier against pathogens and environmental insults. The factors controlling microglia recruitment from the blood remain elusive and the direct circulating microglia precursor has not yet been identified in vivo. Using a panel of bone marrow chimeric and adoptive transfer experiments, we found that circulating Ly-6ChiCCR2+ monocytes were preferentially recruited to the lesioned brain and differentiated into microglia. Notably, microglia engraftment in CNS pathologies, which are not associated with overt blood-brain barrier disruption, required previous conditioning of brain (for example, by direct tissue irradiation). Our results identify Ly-6ChiCCR2+ monocytes as direct precursors of microglia in the adult brain and establish the importance of local factors in the adult CNS for microglia engraftment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Brain-specific macrophages (microglia) have an immunomarker profile similar to that of resident blood monocytes.
Figure 2: Normal development, morphology and function of microglia in the absence of CCR2.
Figure 3: Strong reduction of Ly-6ChiCCR2+ monocytes leads to substantially reduced numbers of engrafted microglia in the CNS.
Figure 4: Engraftment of donor-derived GFP+Ly-6ChiCCR2+ monocytes and differentiation into microglia requires a conditioned CNS.
Figure 5: Immigration of Ly-6Chi monocytes into the brain during cuprizone-induced demyelination requires host conditioning.
Figure 6: Adoptively transferred Ly-6ChiCCR2+ monocytes selectively migrate to the demyelinated area in the conditioned CNS.
Figure 7: Selective recruitment of donor-derived Ly-6ChiCCR2+ monocytes after axotomized facial nucleus occurs only in conditioned CNS.

Similar content being viewed by others

References

  1. Hanisch, U.K. Microglia as a source and target of cytokines. Glia 40, 140–155 (2002).

    Article  Google Scholar 

  2. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    Article  CAS  Google Scholar 

  3. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    Article  CAS  Google Scholar 

  4. Streit, W.J., Walter, S.A. & Pennell, N.A. Reactive microgliosis. Prog. Neurobiol. 57, 563–581 (1999).

    Article  CAS  Google Scholar 

  5. Simard, A.R., Soulet, D., Gowing, G., Julien, J.P. & Rivest, S. Bone marrow–derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489–502 (2006).

    Article  CAS  Google Scholar 

  6. Hickey, W.F. & Kimura, H. Perivascular microglial cells of the CNS are bone marrow–derived and present antigen in vivo. Science 239, 290–292 (1988).

    Article  CAS  Google Scholar 

  7. Hickey, W.F., Vass, K. & Lassmann, H. Bone marrow–derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J. Neuropathol. Exp. Neurol. 51, 246–256 (1992).

    Article  CAS  Google Scholar 

  8. Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7, 1356–1361 (2001).

    Article  CAS  Google Scholar 

  9. Wehner, T. et al. Bone marrow-derived cells expressing green fluorescent protein under the control of the glial fibrillary acidic protein promoter do not differentiate into astrocytes in vitro and in vivo. J. Neurosci. 23, 5004–5011 (2003).

    Article  CAS  Google Scholar 

  10. Williams, A.E., Lawson, L.J., Perry, V.H. & Fraser, H. Characterization of the microglial response in murine scrapie. Neuropathol. Appl. Neurobiol. 20, 47–55 (1994).

    Article  CAS  Google Scholar 

  11. Priller, J. et al. Early and rapid engraftment of bone marrow–derived microglia in scrapie. J. Neurosci. 26, 11753–11762 (2006).

    Article  CAS  Google Scholar 

  12. Djukic, M. et al. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129, 2394–2403 (2006).

    Article  Google Scholar 

  13. Heppner, F.L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146–152 (2005).

    Article  CAS  Google Scholar 

  14. Kokovay, E. & Cunningham, L.A. Bone marrow–derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson's disease. Neurobiol. Dis. 19, 471–478 (2005).

    Article  CAS  Google Scholar 

  15. Malm, T.M. et al. Bone marrow–derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol. Dis. 18, 134–142 (2005).

    Article  CAS  Google Scholar 

  16. Stalder, A.K. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25, 11125–11132 (2005).

    Article  CAS  Google Scholar 

  17. Massengale, M., Wagers, A.J., Vogel, H. & Weissman, I.L. Hematopoietic cells maintain hematopoietic fates upon entering the brain. J. Exp. Med. 201, 1579–1589 (2005).

    Article  CAS  Google Scholar 

  18. van Furth, R. & Cohn, Z.A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    Article  CAS  Google Scholar 

  19. Gordon, S. & Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

    Article  CAS  Google Scholar 

  20. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  Google Scholar 

  21. Grage-Griebenow, E., Flad, H.D. & Ernst, M. Heterogeneity of human peripheral blood monocyte subsets. J. Leukoc. Biol. 69, 11–20 (2001).

    CAS  PubMed  Google Scholar 

  22. Sunderkotter, C. et al. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J. Immunol. 172, 4410–4417 (2004).

    Article  Google Scholar 

  23. Swirski, F.K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).

    Article  CAS  Google Scholar 

  24. Sedgwick, J.D. et al. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc. Natl. Acad. Sci. U.S.A 88, 7438–7442 (1991).

    Article  CAS  Google Scholar 

  25. Serbina, N.V. & Pamer, E.G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    Article  CAS  Google Scholar 

  26. Kuziel, W.A. et al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc. Natl. Acad. Sci. U.S.A 94, 12053–12058 (1997).

    Article  CAS  Google Scholar 

  27. Furuya, T. et al. Establishment of modified chimeric mice using GFP bone marrow as a model for neurological disorders. Neuroreport 14, 629–631 (2003).

    Article  Google Scholar 

  28. Linard, C. et al. Acute induction of inflammatory cytokine expression after gamma-irradiation in the rat: effect of an NF-kappaB inhibitor. Int. J. Radiat. Oncol. Biol. Phys. 58, 427–434 (2004).

    Article  CAS  Google Scholar 

  29. Francois, S. et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 24, 1020–1029 (2006).

    Article  Google Scholar 

  30. Kondo, A., Nakano, T. & Suzuki, K. Blood-brain barrier permeability to horseradish peroxidase in twitcher and cuprizone-intoxicated mice. Brain Res. 425, 186–190 (1987).

    Article  CAS  Google Scholar 

  31. Bakker, D.A. & Ludwin, S.K. Blood-brain barrier permeability during Cuprizone-induced demyelination. Implications for the pathogenesis of immune-mediated demyelinating diseases. J. Neurol. Sci. 78, 125–137 (1987).

    Article  CAS  Google Scholar 

  32. McMahon, E.J., Suzuki, K. & Matsushima, G.K. Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. J. Neuroimmunol. 130, 32–45 (2002).

    Article  CAS  Google Scholar 

  33. Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999).

    Article  CAS  Google Scholar 

  34. Wegiel, J. et al. Reduced number and altered morphology of microglial cells in colony stimulating factor-1–deficient osteopetrotic op/op mice. Brain Res. 804, 135–139 (1998).

    Article  CAS  Google Scholar 

  35. Beers, D.R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021–16026 (2006).

    Article  CAS  Google Scholar 

  36. Vallieres, L. & Sawchenko, P.E. Bone marrow–derived cells that populate the adult mouse brain preserve their hematopoietic identity. J. Neurosci. 23, 5197–5207 (2003).

    Article  CAS  Google Scholar 

  37. Simard, A.R. & Rivest, S. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J. 18, 998–1000 (2004).

    Article  CAS  Google Scholar 

  38. Biffi, A. et al. Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J. Clin. Invest. 113, 1118–1129 (2004).

    Article  CAS  Google Scholar 

  39. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).

    Article  CAS  Google Scholar 

  40. Remington, L.T., Babcock, A.A., Zehntner, S.P. & Owens, T. Microglial recruitment, activation and proliferation in response to primary demyelination. Am. J. Pathol. 170, 1713–1724 (2007).

    Article  Google Scholar 

  41. Yamamoto, M. et al. Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. Am. J. Pathol. 166, 1475–1485 (2005).

    Article  CAS  Google Scholar 

  42. Prinz, M. et al. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425, 957–962 (2003).

    Article  CAS  Google Scholar 

  43. Prinz, M. et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 116, 456–464 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997).

    Article  CAS  Google Scholar 

  46. Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

    Article  CAS  Google Scholar 

  47. Mack, M. et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 166, 4697–4704 (2001).

    Article  CAS  Google Scholar 

  48. Merkler, D. et al. Multicontrast MRI of remyelination in the central nervous system. NMR Biomed. 18, 395–403 (2005).

    Article  Google Scholar 

  49. van Loo, G. et al. Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat. Immunol. 7, 954–961 (2006).

    Article  CAS  Google Scholar 

  50. Prinz, M. & Hanisch, U.K. Murine microglial cells produce and respond to interleukin-18. J. Neurochem. 72, 2215–2218 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank O. Kowatsch, M. Schedensack, E. Pralle, P. Grämmel and S. Blumenau for excellent technical assistance. We thank S. Jung (Rehovot, Israel) for scientific input. This work was supported by grants from Gemeinnützige Hertie-Stiftung to M.P. and D.M., Deutsche Forschungsgemeinschaft (SFB 507 A5 and PR 577) to J.P. and M.P. This project was supported by the DFG research Center for Molecular Physiology of the Brain Göttingen, but support was unfortunately discontinued. M.H. is supported by the Swiss MS Society and the Prof. Dr. Max-Cloëtta Foundation. A.M. and H.S. are fellows of the Gertrud Reemtsma Foundation.

Author information

Author notes

  1. Josef Priller and Marco Prinz: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Neuropathology, Georg August University, Göttingen, Germany

    Alexander Mildner, Hauke Schmidt, Doron Merkler, Uwe-Karsten Hanisch, Wolfgang Brück & Marco Prinz

  2. Department of Radiation Oncology, Georg August University, Göttingen, Germany

    Mirko Nitsche

  3. Department of Internal Medicine, University of Regensburg, Regensburg, Germany

    Matthias Mack

  4. Institute of Neuropathology, Universitätsspital, Zurich, Switzerland

    Mathias Heikenwalder

  5. Institute for Multiple Sclerosis Research, Georg August University, Göttingen, Germany

    Wolfgang Brück

  6. Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Germany

    Josef Priller

Authors
  1. Alexander Mildner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hauke Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mirko Nitsche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Doron Merkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Uwe-Karsten Hanisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthias Mack
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mathias Heikenwalder
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wolfgang Brück
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Josef Priller
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marco Prinz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.M., H.S., M.N., D.M., U.-K.H., J.P. and M.P. conducted the experiments. M.M., M.H. and W.B. provided reagents and scientific input. A.M., J.P. and M.P. designed the experiments and wrote the manuscript.

Corresponding author

Correspondence to Marco Prinz.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 (PDF 119 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mildner, A., Schmidt, H., Nitsche, M. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10, 1544–1553 (2007). https://doi.org/10.1038/nn2015

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn2015

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing