Abstracts

Rationale: Neuroinflammation and systemic inflammation play pivotal roles in both epileptogenesis and pro-epileptogenesis in temporal lobe epilepsy (TLE). The intricate interplay between peripheral CD4+ T cells and central microglia orchestrates the dynamic “systemic-central” immune response in TLE. Yet, the precise molecular mechanisms governing the interaction between neuroinflammation and systemic inflammation in TLE remains elusive. Our preliminary findings, revealing an imbalance in Th1/Th2 subsets in the periphery and the release of microglia-related cytokines in TLE patients, spurred out hypothesis.


Methods: This study enrolled a total of 27 patients with temporal lobe epilepsy who were in treatment in Xiangya Hospital, Central South University, from December 01, 2022, to January 31, 2023. Combined with medical history, EEG and imaging data, these patients were diagnosed with temporal lobe epilepsy according to the diagnostic manual from the International League Against Epilepsy by two trained epileptologists. The TLE rats in the chronic phase were anaesthetized. Single-cell suspensions from the brain tissue and blood were prepared.


Results: We propose that this peripheral Th1/Th2 imbalance may influence neuroinflammation by mediating M1/M2 polarization within epileptic foci and distant brain regions. In Li-pilocarpine-induced TLE rats, we confirmed peripheral Th1/Th2 imbalance and observed corresponding neuro- and systemic responses. Particularly noteworthy was the spatial proximity of CD4+ T cells, infiltrating through seizures-induced comprise blood-brain barrier (BBB), to activated microglia surrounding epileptic foci. Intravenous depletion and reinfusion of peripheral CD4+T cells modulated central microglial M1/M2 polarization and altered the secretion of neuroinflammatory cytokines (INF-γ and IL-4) in TLE. Moreover, mRNA sequencing of human brain epileptogenic lesions identified Notch1 as a key regulator of Th1/Th2 differentiation, CD4+ T cell recruitment to brain infiltration sites, microglial activation, seizure frequency, and long-term cognition.


Conclusions: Our study underscores the significance of Th1/Th2 imbalance in “echoing” M1/M2 phenotypes and their concerted modulation of the “neuro-systemic“ response to TLE. Importantly, it highlights the therapeutic potential of Notch1 as a target for TLE treatment.


Funding: This study was supported by National Key Research and Development Program of China (2022YFC2503804), National Natural Science Foundation of China (82071461; 82271503), China Postdoctoral Science Foundation (No:2023M733958). the Youth Science Foundation of Xiangya Hospital (No. 2023Q14).