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Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool

Nature Neuroscience volume 14, pages 1142–1149 (2011)Cite this article

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Abstract

In multiple sclerosis and the experimental autoimmune encephalitis (EAE) mouse model, two pools of morphologically indistinguishable phagocytic cells, microglia and inflammatory macrophages, accrue from proliferating resident precursors and recruitment of blood-borne progenitors, respectively. Whether these cell types are functionally equivalent is hotly debated, but is challenging to address experimentally. Using a combination of parabiosis and myeloablation to replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor–dependent recruitment of monocytes to the CNS blocked EAE progression, suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that, although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, and therefore do not ultimately contribute to the resident microglial pool. In conclusion, we identified two distinct subsets of myelomonocytic cells with distinct roles in neuroinflammation and disease progression.

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Figure 1: Irradiation and separation of parabiotic mice leads to peripheral blood chimerism in the absence of donor cell entry into the CNS.
Figure 2: Monocytic infiltration correlates with progression to paralytic stages of EAE.
Figure 3: Blood-derived infiltrating cells retain monocyte characteristics during progression to paralytic disease.
Figure 4: Kinetics of microglia expansion and blood-derived monocyte infiltration in EAE.
Figure 5: Blocking monocyte infiltration prevents EAE progression.
Figure 6: Blood-borne inflammatory cell infiltration is transient.
Figure 7: Uncommitted stem or progenitor cells, but not myelomonocytic-committed hematopoietic progenitors, contribute to resident microglia in irradiated-transplanted recipients.

References

  1. Kreutzberg, G.W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).

    Article  CAS  PubMed  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  PubMed  Google Scholar 

  3. Raivich, G. Like cops on the beat: the active role of resting microglia. Trends Neurosci. 28, 571–573 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Lawson, L.J., Perry, V.H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).

    Article  CAS  PubMed  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  PubMed  Google Scholar 

  7. 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  PubMed  Google Scholar 

  8. Hess, D.C. et al. Hematopoietic origin of microglial and perivascular cells in brain. Exp. Neurol. 186, 134–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W. & Rossi, F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hickey, W.F. Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation. Brain Pathol. 1, 97–105 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Hickey, W.F., Hsu, B.L. & Kimura, H. T-lymphocyte entry into the central nervous system. J. Neurosci. Res. 28, 254–260 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Swanborg, R.H. Experimental autoimmune encephalomyelitis in rodents as a model for human demyelinating disease. Clin. Immunol. Immunopathol. 77, 4–13 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Steinman, L., Martin, R., Bernard, C., Conlon, P. & Oksenberg, J.R. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25, 491–505 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Santambrogio, L. et al. Developmental plasticity of CNS microglia. Proc. Natl. Acad. Sci. USA 98, 6295–6300 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ulvestad, E. et al. Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells. J. Leukoc. Biol. 56, 732–740 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Ponomarev, E.D., Shriver, L.P., Maresz, K. & Dittel, B.N. Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J. Neurosci. Res. 81, 374–389 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Bauer, J. et al. The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis. Glia 15, 437–446 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Huitinga, I., van Rooijen, N., de Groot, C.J., Uitdehaag, B.M. & Dijkstra, C.D. Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. J. Exp. Med. 172, 1025–1033 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Brosnan, C.F., Bornstein, M.B. & Bloom, B.R. The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. J. Immunol. 126, 614–620 (1981).

    CAS  PubMed  Google Scholar 

  22. Izikson, L., Klein, R.S., Charo, I.F., Weiner, H.L. & Luster, A.D. Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J. Exp. Med. 192, 1075–1080 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fife, B.T., Huffnagle, G.B., Kuziel, W.A. & Karpus, W.J. CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J. Exp. Med. 192, 899–905 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mildner, A. et al. CCR2+ Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

    Article  PubMed  Google Scholar 

  25. King, I.L., Dickendesher, T.L. & Segal, B.M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kennedy, D.W. & Abkowitz, J.L. Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood 90, 986–993 (1997).

    CAS  PubMed  Google Scholar 

  27. Li, Y.Q., Chen, P., Jain, V., Reilly, R.M. & Wong, C.S. Early radiation-induced endothelial cell loss and blood-spinal cord barrier breakdown in the rat spinal cord. Radiat. Res. 161, 143–152 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Diserbo, M. et al. Blood-brain barrier permeability after gamma whole-body irradiation: an in vivo microdialysis study. Can. J. Physiol. Pharmacol. 80, 670–678 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Mildner, A. et al. Microglia in the adult brain arise from Ly-6Chi CCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Wright, D.E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Mason, D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol. Today 12, 57–60 (1991).

    Article  CAS  PubMed  Google Scholar 

  32. Bukilica, M. et al. Stress-induced suppression of experimental allergic encephalomyelitis in the rat. Int. J. Neurosci. 59, 167–175 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Streit, W.J. Microglia and the response to brain injury. Ernst Schering Res. Found. Workshop 39, 11–24 (2002).

    Google Scholar 

  34. Krall, W.J., Challita, P.M., Perlmutter, L.S., Skelton, D.C. & Kohn, D.B. Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation. Blood 83, 2737–2748 (1994).

    CAS  PubMed  Google Scholar 

  35. 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  PubMed  PubMed Central  Google Scholar 

  36. Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2–red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Carson, M.J., Thrash, J.C. & Walter, B. The cellular response in neuroinflammation: the role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin. Neurosci. Res. 6, 237–245 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Engelhardt, B. Molecular mechanisms involved in T cell migration across the blood-brain barrier. J. Neural Transm. 113, 477–485 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Benveniste, E.N. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J. Mol. Med. 75, 165–173 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Bauer, J., Sminia, T., Wouterlood, F.G. & Dijkstra, C.D. Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis. J. Neurosci. Res. 38, 365–375 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Kim, J.V., Kang, S.S., Dustin, M.L. & McGavern, D.B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Getts, D.R. et al. Ly-6C+ 'inflammatory monocytes' are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis. J. Exp. Med. 205, 2319–2337 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nagai, Y. et al. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity 24, 801–812 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wujek, J.R. et al. Axon loss in the spinal cord determines permanent neurological disability in an animal model of multiple sclerosis. J. Neuropathol. Exp. Neurol. 61, 23–32 (2002).

    Article  PubMed  Google Scholar 

  46. Luster, A.D., Alon, R. & von Andrian, U.H. Immune cell migration in inflammation: present and future therapeutic targets. Nat. Immunol. 6, 1182–1190 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Yednock, T.A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356, 63–66 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Miller, D.H. et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348, 15–23 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Steinman, L. Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat. Rev. Drug Discov. 4, 510–518 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Langer-Gould, A., Atlas, S.W., Green, A.J., Bollen, A.W. & Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 353, 375–381 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank B. Chua, T. Godbey, K. Ranta, M. Cowan, L. Rollins and the Biomedical Research Center animal unit personnel for advice and help on animal welfare. We thank A. Johnson, C.K. Chang, J. Kang and D. Mahdaviani for their technical help. This work was supported by Canadian Institute for Health Research (CIHR, MOP 81382) grants and a grant from the Multiple Sclerosis Society of Canada to F.M.V.R., a Neuromuscular Research Partnership grant from the CIHR, a grant from the Amyotrophic Lateral Sclerosis Society of Canada and Muscular Dystrophy Canada to C.K. and F.M.V.R. (JNM-69682), a Collaborative Health Research grant from the CIHR and the Natural Science and Engineering Research Council of Canada to C.K. and F.M.V.R. (CHRP 299119), and a research grant from the Multiple Sclerosis Society of Canada to K.M.M. K.M.M. is a Michael Smith Foundation for Health Research Senior Scholar. B.A is supported by a Michael Smith Foundation Senior Graduate Studentship and a CIHR–Amyotrophic Lateral Sclerosis Doctoral Research Award. J.L.B. is supported by a Multiple Sclerosis Society of Canada Postdoctoral Research Fellowship. This research was undertaken, in part, thanks to funding from the Canadian Research Chairs program to F.M.V.R.

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  1. Charles Krieger

    Present address: Present address: Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada, and Division of Neurology, Department of Medicine, Neuromuscular Disease Unit, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada.,

Authors and Affiliations

  1. University of British Columbia, Biomedical Research Centre, Vancouver, British Columbia, Canada

    Bahareh Ajami, Jami L Bennett, Charles Krieger, Kelly M McNagny & Fabio M V Rossi

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Contributions

B.A. designed and conducted all of the experiments, interpreted the data and wrote the manuscript. J.L.B. conducted the EAE induction and participated in the writing of the manuscript. C.K. and K.M.M. participated in the writing of the manuscript. F.M.V.R. designed and interpreted experiments and wrote the manuscript.

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Correspondence to Fabio M V Rossi.

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Ajami, B., Bennett, J., Krieger, C. et al. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14, 1142–1149 (2011). https://doi.org/10.1038/nn.2887

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