Status epilepticus (SE) is a frequent neurological emergency that can reduce the quality of life of those affected, produce cognitive deficits, and result in the development of epilepsy. Brain inflammation is an invariable feature of seizure activity and is believed to contribute to neuronal demise and exacerbate the deleterious behavioral consequences of unabated seizures. However, the involvement of blood-borne immune cells in the brain's inflammatory reaction after seizures remains unresolved. We have recently identified a subclass of circulating monocytes that invades brain tissue after seizures. Our findings indicate that blocking monocyte infiltration, via Ccr2 knockout, reduces the deleterious consequences of SE. These results prompt us to ask whether brain-invading monocytes are a novel therapeutic target to attenuate the adverse effects of seizures, alleviate cognitive dysfunction, and inhibit the development of epilepsy after SE. My hypothesis is that microglia-driven recruitment of brain-invading monocytes is a strong driver of SE-induced neurobehavioral deficits and epileptogenesis in the weeks following SE because pro-inflammatory monocytes migrate across the BBB promoting albumin extravasation into the brain. The lessons gleaned from completion of the proposed studies will lead to insights into myeloid cell biology in epilepsy as well as brain disease in general. The proposed studies will determine how the peripheral immune system can impact central immune reactions and contribute to co-morbidities, leading to decreased quality of life in individuals afflicted with epilepsy. Utilizing multiple techniques, my specific aims are designed to investigate and validate important components of this hypothesis.
Aim 1. To test the hypothesis that brain-infiltrating monocytes engraft in the brain and maintain their own pro-inflammatory profile, exacerbating a pro-inflammatory response in microglia.
Aim 2. To test the hypothesis that albumin extravasation is reliant on monocyte migration across the BBB.
Aim 3. To determine if blocking monocyte brain entry exerts antiepileptogenic or disease modifying effects after SE. If our aims are achieved, then this would support continued efforts for targeting peripheral monocytes with therapies, which could have a significant impact on reducing the burden of neurological disease, a major mission of NINDS.
Multiple lines of evidence have demonstrated that a multidimensional inflammatory response ensues after the prolonged seizures of status epilepticus. We have recently provided evidence that peripheral monocyte infiltration into the brain also mediates an important role, whereby blocking monocyte invasion attenuates neuroinflammation, reduces neuronal injury, prevents erosion of the blood-brain barrier, and enhances weight regain. The current interdisciplinary studies seek to determine if brain-infiltrating monocytes exacerbate a pro- inflammatory response in microglia, pharmacological inhibition of monocyte brain entry also provides beneficial outcomes, and ask if monocytes hasten behavioral decline and promote epileptogenesis.