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

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

Abstract

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.

Keywords: Theiler’s virus; epilepsy; hippocampus; monocytes; myeloid cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11b Antigen / immunology
  • CD11b Antigen / metabolism
  • CX3C Chemokine Receptor 1 / genetics
  • CX3C Chemokine Receptor 1 / immunology*
  • Disease Models, Animal
  • Encephalitis, Viral / immunology*
  • Encephalitis, Viral / pathology
  • Encephalitis, Viral / virology
  • Female
  • Hippocampus / cytology
  • Hippocampus / immunology
  • Hippocampus / pathology
  • Humans
  • Leukocyte Common Antigens / immunology
  • Leukocyte Common Antigens / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / cytology
  • Microglia / immunology
  • Microglia / pathology
  • Monocytes / immunology
  • Monocytes / pathology
  • Neurodegenerative Diseases / immunology*
  • Neurodegenerative Diseases / pathology
  • Neurons / immunology
  • Neurons / pathology
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / immunology*
  • Seizures / immunology*
  • Seizures / pathology
  • Seizures / virology
  • Theilovirus / isolation & purification

Substances

  • CD11b Antigen
  • CX3C Chemokine Receptor 1
  • Ccr2 protein, mouse
  • Cx3cr1 protein, mouse
  • Receptors, CCR2
  • Leukocyte Common Antigens
  • Ptprc protein, mouse