M2 polarization of neuroinflammation as a new approach targeting temporal lobe epilepsy

Epilepsy is a neurological disorder affecting about 60 million people worldwide. It is charactised by recurrent unprovoked seizures. Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsies, is not controlled by current anti-epileptic treatements in around 1/3rd of the patients. An epileptogenic insult leads to a strong inflammatory response characterized by activation of innate brain immune cells as well as migration of immune cells from the peripheral blood due to a compromised blood-brain barrier. These events could induce epileptogenesis by affecting neurodegeneration, reorganization of neuronal circuits, neurogenesis as well as directly promoting the neuronal excitability. An inflammatory response consists of an initial acute classical activation (M1) of the immune cells that leads to release of pro-inflammatory cytokines that may promote disease progression. This is followed by an M2 alternate activation that releases anti-inflammatory cytokines such as IL-13 that initiates repair mechanisms. The goal of this project is to inhibit the epileptogenesis following an initial brain insult by altering the M1/M2 balance of the brain inflammation towards the protective M2 phase. We hypothesize that promoting the M2 activation of immune cells would inhibit development of epileptic seizures in animal models. In this proposal, we aim to administer genetically modified IL-13 expressing M2a polarized macrophages in the mouse brain, at day 2, after the induction of kainic acid induced status epilepticus, a commonly used model of MTLE. We also aim to utilize the seizure-induced leakage in the blood-brain barrier for the transmigration of modified M2 macrophages into the brain following systemic administration. We expect to observe a protective effect of this treatment on neuroinflammation and other neuropathological processes induced by the status epilepticus. More funding will be applied for with an aim to test whether modulating the M1/M2 polarization of brain inflammation during epileptogenesis would alter the development of epileptic seizures in this mouse model. This project could provide novel approaches for the treatment and prevention of epilepsy as well as evaluate the possibility of utilizing systemically delivered macrophages for delivery of therapeutic agents into the epileptic brain.

Keywords:EPILEPSY MODEL, EPILEPSY

Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing