Abstract
Mesial temporal lobe epilepsy (MTLE) is characterized by a hypersynchronization of the activity of neural networks of deep brain structures involved in specific forms of memory and emotions. This neuronal dysfunction, which results in spontaneous focal recurrent seizures, is the main target of current treatments. 70% of patients do not respond to these treatments and the only curative option is the surgical resection of the epileptic focus. It is therefore urgent to better understand the different mechanisms involved in MTLE in order to identify new therapeutic targets.My research focuses on the neuroinflammatory response associated with MTLE. The epileptogenic process is accompanied by a glial reactivity that promotes a deleterious pro-inflammatory microenvironment, amplified by a blood-brain barrier (BBB) dysfunction. The leukocyte infiltrate observed in patients with MTLE suggests a potential interaction between leukocytes, BBB cells and brain parenchyma. The frequency of seizures generally increases as these brain lesions worsen, suggesting that the seizures themselves may have a pathogenic effect on the brain tissue. However, data obtained in humans, where the areas of seizure propagation are not always injured, suggest that seizures do not cause damage. This phenomenon could be explained by the existence of endogenous protective mechanisms that would limit the harmful effects of network hyperexcitability, thus preserving the tissue from damage.There are still few data showing that this deleterious pro-inflammatory response is partly counteracted by an endogenous anti-inflammatory component involving in particular microglia and T cells. Our working hypothesis is that the interaction between microglia and T cells is responsible for the protective anti-inflammatory effect observed in epilepsy. We have observed that in a mouse model of MTLE, the absence of T cells (CD3ԑ -/- mice) is accompanied by the loss of an anti-inflammatory response from microglia, an increase of seizure activity and tissue damage in areas of seizure propagation. These observations suggest that T cells are essential for driving a microglial anti-inflammatory phenotype, limiting seizures, and protecting areas of seizure spreading from tissue damage.The phenocopy of the CD3ԑ-/- phenotype by performing, acute functional inactivation of T regulatory cells (Tregs, essential for immune homeostasis), suggests that this cell is responsible for the polarization of microglia towards a protective anti-inflammatory phenotype. The existence of a communication between Treg and microglia was tested by a microglial depletion experiment that reproduced the phenotype of mice lacking T cells. We demonstrate for the first time a simultaneous involvement of microglia and Tregs in endogenous anti-inflammatory mechanisms that prove to be protective. These results support the hypothesis that spontaneous seizures by themselves do not damage the brain.The clinical relevance of this project will be based on the possibility of testing in humans, new pro- and anti-inflammatory biomarkers validated on our mouse model. Continuing this research would thus contribute to the cooperation between researchers and clinicians, which is essential for a better understanding of the physiopathology. This potential translation of my results to the clinic will open the way to the development of new anti-inflammatory strategies, bypassing the drug resistance associated with anti-epileptic drugs that target neurons, and helping to improve the treatment of MTLE.