Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

Nicholas H. Varvel*, Jonas J. Neher, Andrea Bosch, Wenyi Wang, Richard M. Ransohoff, Richard J. Miller, Raymond Dingledine

*Corresponding author for this work

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do not infiltrate the healthy CNS, monocytes can enter the brain in response to injury and contribute to the immune response. We examined the cellular components of innate immune inflammation in the days following SE by discriminating microglia vs. brain-infiltrating monocytes. Chemokine receptor 2 (CCR2+) monocytes invade the hippocampus between 1 and 3 d after SE. In contrast, only an occasional CD3+ T lymphocyte was encountered 3 d after SE. The initial cellular sources of the chemokine CCL2, a ligand for CCR2, included perivascular macrophages and microglia. The induction of the proinflammatory cytokine IL-1β was greater in FACS-isolated microglia than in brain-invading monocytes. However, Ccr2 knockout mice displayed greatly reduced monocyte recruitment into brain and reduced levels of the proinflammatory cytokine IL-1β in hippocampus after SE, which was explained by higher expression of the cytokine in circulating and brain monocytes in wild-type mice. Importantly, preventing monocyte recruitment accelerated weight regain, reduced BBB degradation, and attenuated neuronal damage. Our findings identify brain-infiltrating monocytes as a myeloid-cell subclass that contributes to neuroinflammation and morbidity after SE. Inhibiting brain invasion of CCR2+ monocytes could represent a viable method for alleviating the deleterious consequences of SE.

Original languageEnglish (US)
Pages (from-to)E5665-E5674
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
StatePublished - Sep 20 2016

Keywords

  • Epileptogenesis
  • Microgliosis
  • Myeloid cell heterogeneity
  • Neuroprotection
  • Seizure

ASJC Scopus subject areas

  • General

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