Blocking the innate immune CD1d/NKT cell axis prevents the development of cortical hyperexcitability and posttraumatic epilepsy.

Abstract

Objective: Posttraumatic epilepsy (PTE) that develops after a traumatic brain injury (TBI) cannot be prevented by current treatments. Although neuroinflammation is involved in epileptogenesis, a potential role for cellular immunity in this process is largely unknown. Natural killer T (NKT) cells are innate-like T lymphocytes that recognize lipid antigens presented by the major histocompatibility complex class I-like CD1d molecule and play a crucial role in regulating immune responses. Herein we examined the role of the CD1d/NKT cell axis in PTE.

Methods: We used an undercut surgery to induce TBI in wild-type (WT) and CD1d-deficient (CD1d knockout [KO], CD1d KO) or NKT cell-deficient (Traj18 KO) mice. A pentylenetetrazol (PTZ) test was used to determine seizure susceptibility in vivo, and field potential recordings were made from cortical slices in vitro. Continuous video and wireless EEG monitoring was undertaken of WT and CD1d KO mice between 5 and 8 weeks after brain injury. Because statins are known to impair antigen presentation by CD1d to NKT cells, we also treated WT mice with simvastatin for 10 days after injury and performed the PTZ test. Immunofluorescence and flow cytometry were used to determine changes in immune cells in brain tissue.

Results: CD1d KO or Traj18 KO TBI mice had a significantly lower seizure susceptibility than WT mice on the PTZ test. CD1d KO mice had a significantly lower rate of detectable epileptiform activities during field potential recording. Video and EEG monitoring showed that CD1d KO TBI mice had a significantly lower frequency of spontaneous epileptic seizures. There was increased infiltration of immune cells, but reduced microgliosis in the brains of these mice. Simvastatin treatment significantly reduced seizure susceptibility in TBI mice.

Significance: Neuroinflammation initiated by the CD1d/NKT cell axis is involved in the development of cortical hyperexcitability and PTE; early treatment with simvastatin following a TBI exerts a prophylactic effect on posttraumatic epileptogenesis by blocking this axis.