Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature

Neurobiol Dis. 2018 May:113:70-81. doi: 10.1016/j.nbd.2018.02.002. Epub 2018 Feb 9.

Abstract

Background: Cerebrovascular dysfunction and inflammation occur in epilepsy. Here we asked whether pericytes, a pivotal cellular component of brain capillaries, undergo pathological modifications during experimental epileptogenesis and in human epilepsy. We evaluated whether pro-inflammatory cytokines, present in the brain during seizures, contribute to pericyte morphological modifications.

Methods: In vivo, unilateral intra-hippocampal kainic acid (KA) injections were performed in NG2DsRed/C57BL6 mice to induce status epilepticus (SE), epileptogenesis, and spontaneous recurrent seizures (SRS). NG2DsRed mice were used to visualize pericytes during seizure progression. The effect triggered by recombinant IL-1β, TNFα, or IL-6 on pericytes was evaluated in NG2DsRed hippocampal slices and in human-derived cell culture. Human brain specimens obtained from temporal lobe epilepsy (TLE) with or without sclerosis (HS) and focal cortical dysplasia (FCD-IIb) were evaluated for pericyte-microglial cerebrovascular assembly.

Results: A disarray of NG2DsRed+ pericyte soma and ramifications was found 72 h post-SE and 1 week post-SE (epileptogenesis) in the hippocampus. Pericyte modifications topographically overlapped with IBA1+ microglia clustering around the capillaries with cases of pericytes lodged within the microglial cells. Microglial clustering around the NG2DsRed pericytes lingered at SRS. Pericyte proliferation (Ki67+) occurred 72 h post-SE and during epileptogenesis and returned towards control levels at SRS. Human epileptic brain tissues showed pericyte-microglia assemblies with IBA1/HLA microglial cells outlining the capillary wall in TLE-HS and FCD-IIb specimens. Inflammatory mediators contributed to pericyte modifications, in particular IL-1β elicited pericyte morphological changes and pericyte-microglia clustering in NG2DsRed hippocampal slices. Modifications also occurred when pro-inflammatory cytokines were added to an in vitro culture of pericytes.

Conclusions: These results indicate the occurrence of pericytosis during seizures and introduce a pericyte-microglial mediated mechanism of blood-brain barrier dysfunction in epilepsy.

Keywords: Blood-brain barrier; Epilepsy; Inflammation; Microglia; Pericytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Blood-Brain Barrier / chemistry
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / physiopathology
  • Cells, Cultured
  • Cerebrovascular Circulation / physiology*
  • Child
  • Child, Preschool
  • Disease Progression*
  • Female
  • Hippocampus / blood supply
  • Hippocampus / chemistry
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Humans
  • Infant
  • Inflammation Mediators / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / chemistry
  • Microglia / metabolism*
  • Pericytes / chemistry
  • Pericytes / metabolism*
  • Seizures / metabolism*
  • Seizures / physiopathology

Substances

  • Inflammation Mediators