Epileptogenesis is a pathological process that transforms a normal brain into an epileptic brain, typically initiated by genetic mutations and neurological insults such as status epilepticus (SE). There is an unmet need to understand epileptogenesis because it remains nearly unpreventable. Brain inflammation triggered by neuronal injury is increasingly recognized as a contributor to epileptogenesis. Microglia, generally considered as resident macrophages, are highly proliferated and activated in response to epileptogenic insults and thought to play a primary role. Besides resident microglia, other immune cells in the peripheral system and CNS lymphatic system also infiltrate the CNS compartment and likely contribute to epileptogenesis. It remains to be understood how CNS resident and non-resident immune cells interact in response to epileptogenic insults and how the injury-triggered changes in the immune network impinge on non-immune cells such as astrocytes and neurons, thereby contributing to epileptogenesis. This proposal is built on our observation that IL22Rα1 is strongly up-regulated in astrocytes in the pilocarpine model of temporal lobe epilepsy. This induction depends on brain inflammation. Moreover, the induction of IL22Rα1 is critically involved in astrogliosis, an excessive proliferation and activation of astrocytes frequently seen in epileptic brains. These findings lead to our central hypothesis, that up-regulation of IL22/IL22Rα1 signaling promotes astrocyte proliferation, which in turn contributes to epileptogenesis. Three specific aims are proposed to test our hypothesis. Aim 1 will determine how IL22Rα1 expression is up-regulated in astrocytes. Aim 2 will elucidate how IL22-producing immune cells are recruited into the CNS compartment. Aim 3 will determine if blocking IL22 signaling attenuates astrogliosis and modifies the process of epileptogenesis. Our study will not only improve our understanding how IL22 signaling regulates epileptogenesis, but could also identify druggable targets to prevent epileptogenesis.

The overarching goal of this proposal is to establish IL22/IL22R1 as a novel signaling axis that regulates the astrocytic reaction, which in turn influences brain homeostasis and promotes epileptogenesis. The results from this study will provide new insights into astrogliosis and lead to new therapeutic targets to combat epilepsy.