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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*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.
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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