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Control of microglial neurotoxicity by the fractalkine receptor

This article has been updated


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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    *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.


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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.

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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).

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