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Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 29, 2016 (received for review March 14, 2016)
Significance
Status epilepticus is a frequent neurological emergency. These unabated seizures reduce quality of life, promote the development of epilepsy, and can cause death. Activation of microglia, the brain’s resident immune cells, is an invariable feature of seizure activity. However, the involvement of blood-borne immune cells in the brain’s inflammatory reaction after seizures remains unresolved. Here we identify a blood cell not normally encountered in the healthy brain, called a monocyte, which invades brain tissue after seizures and contributes to inflammation. Blocking brain entry of the blood monocytes was beneficial, reducing neuronal damage and accelerating weight regain. Treatment strategies aimed at inhibiting peripheral immune cells from entering the brain after seizures could be beneficial.
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.
Footnotes
- ↵1To whom correspondence should be addressed. Email: nvarvel{at}emory.edu.
Author contributions: N.H.V. and R.D. designed research; N.H.V., J.J.N., A.B., and W.W. performed research; R.M.R. and R.J.M. contributed new reagents/analytic tools; N.H.V., J.J.N., R.M.R., R.J.M., and R.D. analyzed data; and N.H.V. and R.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1604263113/-/DCSupplemental.
CCR2 monocytes infiltrate after status epilepticus
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