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

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. myeloid cell heterogeneity | epileptogenesis | neuroprotection | seizure | microgliosis S tatus epilepticus (SE) is a serious medical emergency that triggers a series of cellular and molecular events that can result in the development of epilepsy, a chronic neurological disorder characterized by a persistently lowered seizure threshold (1). The early consequences of SE in rodents include a robust neuroinflammatory response, selective neuronal degeneration, and transient opening of the blood-brain barrier (BBB), leading to later cognitive decline. Although the neuroinflammatory features of SE in man are less well known, extravasation of albumin into the brain was observed for patients who died in SE (2), elevated cerebrospinal fluid levels of the cytokines IL-6, IL-8, and CXCL10 are typically found in patients with refractory SE compared with patients with other inflammatory neurologic disorders (3), and intense gliosis (both astrocytes and microglia) was observed in the temporal cortex of a patient with new-onset focal seizures that progressed to refractory SE (4). These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflamma...

Unraveling the host's immune response to infection: Seeing is believing

“…Interestingly, it was found that inhibiting the recruitment of monocytes, but not neutrophils, significantly reduced signs of neuroinflammation and cognitive impairment after infection . This is in line with numerous recent non‐IVM publications implicating monocytes in brain inflammation …”

Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus

“…We investigated whether IN administration of A1-exosomes after SE would result in targeting of these exosomes into the hippocampus, the region exhibiting intense hyperactivity of neurons, increased oxidative stress, and inflammation with infiltration of peripheral monocytes during and/or after SE (5,12). We administered PKH26-labeled A1-exosomes via IN route (15 μg, ∼7.5 × 10 9 ) immediately after the termination of 2 h of SE by an injection of diazepam.…”

“…It can produce substantial neurodegeneration, blood-brain barrier disruption, and inflammation in the hippocampus if not extinguished quickly by antiepileptic drug (AED) treatment (3)(4)(5). An episode of extended SE is sufficient to cause chronic hippocampus dysfunction, exemplified by persistent inflammation with activation of microglia and monocyte infiltration, loss of sizable fractions of several subclasses of inhibitory interneurons, aberrant and waned neurogenesis, hippocampus-dependent cognitive and memory impairments, and chronic epilepsy (5)(6)(7)(8)(9)(10)(11)(12). Numerous situations such as head trauma, stroke, Alzheimer's disease, brain tumor, and encephalitis can engender SE.…”

Microglial proliferation and monocyte infiltration contribute to microgliosis following status epilepticus

“…Recent studies, however, showed that in addition to resident microglia, infiltrating immune cells (i.e. , monocytes, leukocytes) invade the hippocampus after seizures and contribute significantly to pathogenesis (Tian et al, ; Varvel et al, ; Zattoni et al, ). In this study, we used complimentary techniques to investigate the source of microgliosis, particularly the respective contribution of monocyte infiltration and local proliferation in epilepsy.…”