Glucocorticoid‐Induced Tumor Necrosis Factor Receptor Ligand: Correlation and Therapeutic Potential for Cognitive Impairment in Temporal Lobe Epilepsy

Immune checkpoint regulators can improve neurological functions in Alzheimer's disease. However, it remains blurred whether these regulators may ameliorate temporal lobe epilepsy (TLE) and TLE-related cognitive impairment. This study analyzed the bulk transcriptomic data of human TLE hippocampi by bioinformatics. The expression of the potential immune checkpoint regulators in the hippocampus was assessed by immunohistochemical staining; the preoperative seizure severity and postoperative cognitive function were evaluated by the National Hospital Seizure Severity Scale (NHS3) and Telephone Interview for Cognitive Status-Modified (TICS-m); the correlation between the target immune checkpoint regulators and TLE-related cognitive impairment was examined by simple linear regression models and the area under the receiver operating characteristic curve (AUC). We first identified glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) as a key immune checkpoint regulator in TLE patients, with an increased intensity of GITRL in epileptic hippocampus (n = 21) compared with that of the control (n = 3). The GITRL intensity was positively correlated with NHS3 score (r² = 0.503, p < 0.001) and negatively with TICS-m total score (r² = 0.456, p < 0.001), specifically, TICS-m memory score (r² = 0.360, p = 0.004), TICS-m language/attention score (r² = 0.319, p = 0.008), and TICS-m orientation score (r² = 0.312, p = 0.008). The AUC showed that the GITRL intensity presented a good predictive performance in discerning patients with a TICS-m score of ≥ 30 (AUC: 0.875, 95% CI, 0.721-1.00; p = 0.013). These findings highlight hippocampal GITRL as a potential predictive marker for TLE-related cognitive impairment.