A TLR4-Associated Microglia–Endothelial Inflammatory Axis in Drug-Resistant Temporal Lobe Epilepsy: Integrated Transcriptomic and Genetic Evidence
- 1The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China
Abstract
Microglia-driven neuroinflammation contributes to epileptogenesis and drug resistance in temporal lobe epilepsy (TLE), but the cellular organization of the neuroinflammatory hub and its coupling to the cerebrovascular endothelium remain unresolved. We performed a retrospective secondary analysis of publicly available datasets, integrating paired hippocampal bulk transcriptomics (GSE134697), an integrated temporal-lobe single-cell/nucleus RNA sequencing (sc/snRNA-seq) atlas (9 patients with drug-resistant TLE and 4 controls), two-sample Mendelian randomization (MR) and summary-based Mendelian randomization (SMR), and independent hippocampal (n = 77) and peripheral blood (n = 141) cohorts. Five candidate neuroimmune hub genes (TGFB1, ICAM1, TLR4, TLR2 and CCL2) were prioritized using a prespecified, threshold-dependent workflow and mapped to a microglia–cerebrovascular endothelium–peripheral myeloid cell axis. sc/snRNA-seq identified an activated endothelial subpopulation, detected only in TLE samples, and expansion of a microglial compartment with disease-associated microglia (DAM)-like features; CellChat and MultiNicheNet prioritized microglia-derived SPP1, C1QA and MIF as candidate mediators of endothelial inflammatory activation via S1PR1/ITGB1, CD93 and CD74. Plasma kynurenine showed a nominally significant association with focal epilepsy in MR (inverse-variance weighted [IVW] OR = 1.96, 95% CI 1.10–3.52, p = 0.024), whereas SMR did not detect genetically predicted effects of TLR4 or TLR2 expression on focal epilepsy risk; these findings do not establish an acquired disease mechanism. A TGFB1 + TLR4 two-gene signature showed exploratory discrimination in an independent hippocampal cohort (area under the receiver operating characteristic curve [AUC] = 0.868), and blood TLR4 was selectively elevated in drug-naïve newly diagnosed patients (AUC = 0.684). Targeted gene set enrichment analysis (GSEA) and molecular docking nominated simvastatin as a repurposing candidate predicted computationally to interact with MD-2; this prediction has not been functionally validated. This multi-cohort study identifies a TLR4-associated microglia–endothelial inflammatory axis in drug-resistant TLE and generates hypotheses for prospective biomarker studies and experimental drug-repurposing research.
Related
- Integrated transcriptomic analysis identifies an AKT1-associated metabolic-inflammatory signature in osteoporosis.
- Integrated toxicogenomic and single-nucleus transcriptomic analyses prioritize SDHB and NDUFAB1 in mitochondrial respiration-associated remodeling during cisplatin-induced acute kidney injury
- Integrated transcriptomic and metabolomic analyses reveal that flavonoid metabolic pathways are associated with petal discoloration in Aquilegia viridiflora s.l.
- Interferon-Associated Inflammatory Remodeling and Oxidative Metabolic Repression Define the Skeletal Muscle Transcriptomic Landscape of δ-Sarcoglycan Deficiency
- Integrated Transcriptomic and Biochemical Analyses Reveal Coordinated Suppression of ER-Associated Survival Signaling and Activation of ROS-Mediated Stress Responses by Oxidized Graphene Quantum Dots in Estrogen Receptor-Positive Breast Cancer
BibTeX
@article{liu2026tlr4associated,
title = {{A TLR4-Associated Microglia–Endothelial Inflammatory Axis in Drug-Resistant Temporal Lobe Epilepsy: Integrated Transcriptomic and Genetic Evidence}},
author = {Zhenglin Liu and Jian Yin},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219960},
url = {https://www.mdpi.com/1422-0067/27/21/9960},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A TLR4-Associated Microglia–Endothelial Inflammatory Axis in Drug-Resistant Temporal Lobe Epilepsy: Integrated Transcriptomic and Genetic Evidence
AU - Zhenglin Liu
AU - Jian Yin
PY - 2026
DA - 2026/11/06
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219960
UR - https://www.mdpi.com/1422-0067/27/21/9960
AB - Microglia-driven neuroinflammation contributes to epileptogenesis and drug resistance in temporal lobe epilepsy (TLE), but the cellular organization of the neuroinflammatory hub and its coupling to the cerebrovascular endothelium remain unresolved. We performed a retrospective secondary analysis of publicly available datasets, integrating paired hippocampal bulk transcriptomics (GSE134697), an integrated temporal-lobe single-cell/nucleus RNA sequencing (sc/snRNA-seq) atlas (9 patients with drug-resistant TLE and 4 controls), two-sample Mendelian randomization (MR) and summary-based Mendelian randomization (SMR), and independent hippocampal (n = 77) and peripheral blood (n = 141) cohorts. Five candidate neuroimmune hub genes (TGFB1, ICAM1, TLR4, TLR2 and CCL2) were prioritized using a prespecified, threshold-dependent workflow and mapped to a microglia–cerebrovascular endothelium–peripheral myeloid cell axis. sc/snRNA-seq identified an activated endothelial subpopulation, detected only in TLE samples, and expansion of a microglial compartment with disease-associated microglia (DAM)-like features; CellChat and MultiNicheNet prioritized microglia-derived SPP1, C1QA and MIF as candidate mediators of endothelial inflammatory activation via S1PR1/ITGB1, CD93 and CD74. Plasma kynurenine showed a nominally significant association with focal epilepsy in MR (inverse-variance weighted [IVW] OR = 1.96, 95% CI 1.10–3.52, p = 0.024), whereas SMR did not detect genetically predicted effects of TLR4 or TLR2 expression on focal epilepsy risk; these findings do not establish an acquired disease mechanism. A TGFB1 + TLR4 two-gene signature showed exploratory discrimination in an independent hippocampal cohort (area under the receiver operating characteristic curve [AUC] = 0.868), and blood TLR4 was selectively elevated in drug-naïve newly diagnosed patients (AUC = 0.684). Targeted gene set enrichment analysis (GSEA) and molecular docking nominated simvastatin as a repurposing candidate predicted computationally to interact with MD-2; this prediction has not been functionally validated. This multi-cohort study identifies a TLR4-associated microglia–endothelial inflammatory axis in drug-resistant TLE and generates hypotheses for prospective biomarker studies and experimental drug-repurposing research.
SN - 1422-0067
ER -