{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T08:13:26Z","timestamp":1792052006046,"version":"4.4.0"},"reference-count":101,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Temporal lobe epilepsy emerges from a cascade of molecular, cellular, and structural disturbances triggered by heterogeneous cerebral insults\u2014including convulsive status epilepticus, viral encephalitis, traumatic brain injury, and blood\u2013brain barrier disruption\u2014that converge on progressive hippocampal reorganization and a chronic predisposition to unprovoked focal seizures. Convergent evidence from chemoconvulsant models, focal intrahippocampal kainate administration, viral encephalitis paradigms, organotypic hippocampal cultures, human iPSC-derived organoids, and resected human tissue shows that innate immune pathways are not secondary epiphenomena but central drivers of epileptogenesis. Pattern-recognition receptors\u2014particularly TLR2, TLR3, TLR4, IL-1R1 and the NLRP3 inflammasome\u2014sense pathogen- and damage-associated molecular motifs, including HMGB1, and initiate MyD88-, NF-\u03baB- and caspase-1\u2013dependent signaling. These cascades acutely amplify IL-1\u03b2, TNF-\u03b1 and IL-6 responses, alter ion-channel phosphorylation states, enhance NMDA- and AMPA-receptor\u2013mediated excitation, and impair GABAergic inhibition, thereby lowering the seizure threshold. Sustained innate immune activation drives microglial M1 polarization, complement-mediated synaptic loss, aberrant neurogenesis, endothelial dysfunction, and persistent astroglial reactivity\u2014mechanisms that reinforce circuit hyperexcitability and enable the transition from provoked to spontaneous recurrent seizures. Targeted interventions\u2014including TLR4 antagonists (TAK-242), IL-1\u2013pathway inhibitors (anakinra; the caspase-1 inhibitor VX-765), NLRP3 inhibitors (MCC950), and complement-directed strategies\u2014reduce seizure burden, mitigate hippocampal atrophy, and, when administered early, attenuate maladaptive network remodeling. Several conventional antiseizure medications, including levetiracetam, also exhibit immunomodulatory properties by modulating microglial activation, suggesting a mechanistic overlap between pharmacological seizure control and immune regulation. Emerging data implicate the TLR7\u2013endogenous retrovirus axis as an upstream determinant of neuroimmune homeostasis, linking impaired surveillance of viral and retroelement activity to glial activation and network instability. Together, these findings position innate immunity as a mechanistically coherent and therapeutically tractable axis in temporal lobe epilepsy. Achieving clinical translation will require immune-phenotype stratification, biomarker-guided timing of intervention, and advances in CNS-targeted delivery. Integrating immunomodulatory approaches with established antiseizure therapies offers a promising route toward disease modification, cognitive preservation, and more precise treatment of drug-resistant epilepsy.<\/jats:p>","DOI":"10.3389\/fphar.2026.1770964","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:38:17Z","timestamp":1770809897000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Innate immune signalling, neuroinflammation and network plasticity in temporal lobe epilepsy"],"prefix":"10.3389","volume":"17","author":[{"given":"Oscar","family":"Arias-Carri\u00f3n","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Neurociencias Cl\u00ednica, Instituto Nacional de Rehabilitaci\u00f3n Luis Guillermo Ibarra Ibarra","place":["Mexico City, Mexico"]},{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud","place":["Mexico City, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julieta","family":"Rodr\u00edguez de Ita","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud","place":["Monterrey, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Philipps-Universit\u00e4t Marburg","place":["Marburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"177646","DOI":"10.1016\/j.ejphar.2025.177646","article-title":"The possible role of neurogenesis activators in temporal lobe epilepsy: state of art and future perspective","volume":"998","author":"Al-Dhahi","year":"2025","journal-title":"Eur. 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