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Control of microglial neurotoxicity by the fractalkine receptor

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Abstract

Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1−/− mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1−/− mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.

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Figure 1: Microglial cells comprise the CX3CR1/GFP+ population.
Figure 2: Cx3cr1−/− mice show increased microglial activation and enhanced neuronal damage after systemic inflammation.
Figure 3: Adoptive transfer studies of microglia by intracranial microinjection.
Figure 4: Adoptive transfer studies using stereotaxic placement of microglial cells.
Figure 5: Enhanced neurotoxic effects of MPTP in Cx3cr1−/− mice.
Figure 6: Microglial activation, neuron loss, hindlimb grip strength and survival in SOD1G93A/Cx3cr1 mice.

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  • 18 June 2006

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Notes

  1. *NOTE: In the version of this article initially published online, Figure 6a showed the wrong image. The error has been corrected for all versions of the article.

References

  1. Harrison, J.K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA 95, 10896–10901 (1998).

    Article  CAS  Google Scholar 

  2. Cook, D.N. et al. Generation and analysis of mice lacking the chemokine fractalkine. Mol. Cell. Biol. 21, 3159–3165 (2001).

    Article  CAS  Google Scholar 

  3. Niess, J.H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    Article  CAS  Google Scholar 

  4. 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 

  5. 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 

  6. Haskell, C.A. et al. Targeted deletion of CX(3)CR1 reveals a role for fractalkine in cardiac allograft rejection. J. Clin. Invest. 108, 679–688 (2001).

    Article  CAS  Google Scholar 

  7. Huang, D. et al. The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. FASEB J. 20, 896–905 (2006).

    Article  CAS  Google Scholar 

  8. Boehme, S.A., Lio, F.M., Maciejewski-Lenoir, D., Bacon, K.B. & Conlon, P.J. The chemokine fractalkine inhibits Fas-mediated cell death of brain microglia. J. Immunol. 165, 397–403 (2000).

    Article  CAS  Google Scholar 

  9. 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 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. Nataf, S. et al. Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages. Am. J. Pathol. 166, 275–286 (2005).

    Article  CAS  Google Scholar 

  13. Takahashi, K., Rochford, C.D. & Neumann, H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647–657 (2005).

    Article  CAS  Google Scholar 

  14. Ito, D. et al. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res. Mol. Brain Res. 57, 1–9 (1998).

    Article  CAS  Google Scholar 

  15. Hulshof, S. et al. CX3CL1 and CX3CR1 expression in human brain tissue: noninflammatory control versus multiple sclerosis. J. Neuropathol. Exp. Neurol. 62, 899–907 (2003).

    Article  CAS  Google Scholar 

  16. Rivest, S. Molecular insights on the cerebral innate immune system. Brain Behav. Immun. 17, 13–19 (2003).

    Article  CAS  Google Scholar 

  17. Carson, M.J., Reilly, C.R., Sutcliffe, J.G. & Lo, D. Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. Am. J. Pathol. 154, 481–494 (1999).

    Article  CAS  Google Scholar 

  18. Rothwell, N. Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav. Immun. 17, 152–157 (2003).

    Article  Google Scholar 

  19. Zujovic, V., Benavides, J., Vige, X., Carter, C. & Taupin, V. Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 29, 305–315 (2000).

    Article  CAS  Google Scholar 

  20. Facchinetti, F. et al. Lack of involvement of neuronal nitric oxide synthase in the pathogenesis of a transgenic mouse model of familial amyotrophic lateral sclerosis. Neuroscience 90, 1483–1492 (1999).

    Article  CAS  Google Scholar 

  21. Kust, B.M., Brouwer, N., Mantingh, I.J., Boddeke, H.W. & Copray, J.C. Reduced p75NTR expression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 4, 100–105 (2003).

    Article  CAS  Google Scholar 

  22. Chapman, G.A. et al. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J. Neurosci. 20, RC87 (2000).

    Article  CAS  Google Scholar 

  23. Meucci, O., Fatatis, A., Simen, A.A. & Miller, R.J. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc. Natl. Acad. Sci. USA [erratum appears in Proc. Natl. Acad. Sci. USA 98, 15393 (2001)] 97, 8075–8080 (2000).

    Article  CAS  Google Scholar 

  24. Mizuno, T., Kawanokuchi, J., Numata, K. & Suzumura, A. Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res. 979, 65–70 (2003).

    Article  CAS  Google Scholar 

  25. Soriano, S.G. et al. Mice deficient in fractalkine are less susceptible to cerebral ischemia-reperfusion injury. J. Neuroimmunol. 125, 59–65 (2002).

    Article  CAS  Google Scholar 

  26. Milligan, E. et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur. J. Neurosci. 22, 2775–2782 (2005).

    Article  CAS  Google Scholar 

  27. Milligan, E.D. et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur. J. Neurosci. 20, 2294–2302 (2004).

    Article  CAS  Google Scholar 

  28. Hoek, R.M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    Article  CAS  Google Scholar 

  29. Wright, G.J. et al. Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 13, 233–242 (2000).

    Article  CAS  Google Scholar 

  30. Lesnik, P., Haskell, C.A. & Charo, I.F. Decreased atherosclerosis in CX3CR1−/− mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest. 111, 333–340 (2003).

    Article  CAS  Google Scholar 

  31. Hundhausen, C. et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 102, 1186–1195 (2003).

    Article  CAS  Google Scholar 

  32. Cybulsky, M.I. & Hegele, R.A. The fractalkine receptor CX3CR1 is a key mediator of atherogenesis. J. Clin. Invest. 111, 1118–1120 (2003).

    Article  CAS  Google Scholar 

  33. McDermott, D.H. et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ. Res. 89, 401–407 (2001).

    Article  CAS  Google Scholar 

  34. Charo, I.F. & Ransohoff, R.M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).

    Article  CAS  Google Scholar 

  35. Sugama, S. et al. Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain Res. 964, 288–294 (2003).

    Article  CAS  Google Scholar 

  36. West, M.J. New stereological methods for counting neurons. Neurobiol. Aging 14, 275–285 (1993).

    Article  CAS  Google Scholar 

  37. Mitsumoto, H. et al. Effects of cardiotrophin-1 (CT-1) in a mouse motor neuron disease. Muscle Nerve 24, 769–777 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge B. Trapp (Cleveland Clinic, Cleveland) for IBA-1 antibodies, W. Stallcup (Burnham Institute, La Jolla, California) for NG-2 antibodies, C. Canasto (Mount Sinai School of Medicine, New York) for technical assistance with CX3CL1 mice, R. Zhang (Mass Spectrometry Core II, Cleveland Clinic) for assistance with MPP+ measurements, C. Shemo (Flow Cytometry Core, Cleveland Clinic) for assistance with flow cytometry, and J. Drazba (Lerner Research Institute Imaging Core, Cleveland Clinic) for assistance with confocal microscopy. R.H. Miller (Case Medical School, Cleveland) provided helpful comments about the manuscript. This work was supported by the US National Institute of Health (NS32151), the Charles A. Dana Foundation, the National Multiple Sclerosis Society (fellowship FG1528-A-1 to A.C.), the Robert Packard Foundation for ALS Research at Johns Hopkins University and the Boye Foundation.

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A.E.C. performed the experimental design of the LPS and MPTP models, and carried out the microglia isolation, tissue staining and microglial transfer experiments. E.P.P. and V.K. carried out the experiments with SODG93A transgenic mice and assisted with manuscript preparation. M.E.S. and S.M.C. assisted in the maintenance of the mouse colony, genotyping, histopathological staining and neuronal counting. I.M.D. assisted in the development of the stereotaxic protocol. D.H. collaborated in the colocalization of lineage markers with the GFP reporter. G.K. assisted with the confocal analyses and imaging. S.D. assisted with stereology methods. R.D. collaborated in the analysis of the gene expression data from nuclease protection assays. J.-C.L. performed the statistical analyses for all experiments. D.N.C., S.J., S.A.L. and D.R.L. generated the highly inbred receptor- and ligand-deficient mouse strains, and assisted with the experimental design and manuscript preparation. R.M.R. provided the basis for the development of the experimental designs. A.E.C. and R.M.R. analyzed the data, interpreted the results and prepared the manuscript.

Corresponding author

Correspondence to Richard M Ransohoff.

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The authors declare no competing financial interests.

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Cardona, A., Pioro, E., Sasse, M. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9, 917–924 (2006). https://doi.org/10.1038/nn1715

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