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Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):E8929-E8938. doi: 10.1073/pnas.1806754115. Epub 2018 Sep 4.

Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures.

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Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany, and the Hannover Medical School, 30625 Hannover, Germany.
Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
Center for Systems Neuroscience, 30559 Hannover, Germany.
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany;


Viral encephalitis is a major risk factor for the development of seizures, epilepsy, and hippocampal damage with associated cognitive impairment, markedly reducing quality of life in survivors. The mechanisms underlying seizures and hippocampal neurodegeneration developing during and after viral encephalitis are only incompletely understood, hampering the development of preventive treatments. Recent findings suggest that brain invasion of blood-born monocytes may be critically involved in both seizures and brain damage in response to encephalitis, whereas the relative role of microglia, the brain's resident immune cells, in these processes is not clear. CCR2 and CX3CR1 are two chemokine receptors that regulate the responses of myeloid cells, such as monocytes and microglia, during inflammation. We used Ccr2-KO and Cx3cr1-KO mice to understand the role of these receptors in viral encephalitis-associated seizures and neurodegeneration, using the Theiler's virus model of encephalitis in C57BL/6 mice. Our results show that CCR2 as well as CX3CR1 plays a key role in the accumulation of myeloid cells in the CNS and activation of hippocampal myeloid cells upon infection. Furthermore, by using Cx3cr1-creER+/-tdTomatoSt/Wt reporter mice, we show that, with regard to CD45 and CD11b expression, some microglia become indistinguishable from monocytes during CNS infection. Interestingly, the lack of CCR2 or CX3CR1 receptors was associated with almost complete prevention of hippocampal damage but did not prevent seizure development after viral CNS infection. These data are compatible with the hypothesis that CNS inflammatory mechanism(s) other than the infiltrating myeloid cells trigger the development of seizures during viral encephalitis.


Theiler’s virus; epilepsy; hippocampus; monocytes; myeloid cells

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