TNF signaling at the brain-heart interface: neurovascular injury and cardiovascular vulnerability in epilepsy

Epilepsy is increasingly viewed as a systemic disorder in which recurrent seizures intersect with vascular, autonomic, respiratory, and cardiac processes to influence cardiovascular vulnerability. Seizure-related neuroinflammation involves multiple interacting mediator pathways, including HMGB1/TLR4-RAGE signaling, inflammasome/IL-1β activation, IL-6/IL-6R-gp130 signaling, albumin/TGF-β signaling following blood-brain barrier (BBB) disruption, and tumor necrosis factor-alpha (TNF-α)/TNF receptor (TNFR) signaling. Within this inflammatory network, TNF/TNFR signaling represents a mechanistically distinct and translationally relevant framework for examining how immune activation intersects with endothelial-barrier dysfunction, neurovascular unit injury, autonomic disturbance, inflammatory communication across neural and cardiovascular compartments, and cardiac vulnerability. This review integrates direct evidence from epilepsy studies with mechanistic insights from related experimental studies of BBB injury, myocardial ischemia-reperfusion injury, cardioprotection, and brain-heart communication. TNF biology is determined by ligand form, receptor subtype, cellular compartment, and disease context. Soluble TNF preferentially engages TNFR1-associated inflammatory and injury-amplifying pathways, whereas transmembrane TNF/TNFR2 signaling may support regulatory or reparative responses in selected settings. In epilepsy, seizure-associated inflammation, BBB dysfunction, glial activation, and autonomic imbalance may interact to increase susceptibility to arrhythmogenic stress, myocardial injury, adverse cardiac remodeling, and cardiorespiratory instability relevant to sudden unexpected death in epilepsy (SUDEP). However, epilepsy-specific evidence directly linking TNF/TNFR signaling to cardiovascular outcomes remains limited, and many mechanistic connections currently rely on converging evidence from neurovascular and cardiovascular research. Future studies should integrate compartment-resolved inflammatory profiling with autonomic, respiratory, electrocardiographic, and cardiac phenotyping to distinguish inflammatory signatures of disease severity from modifiable contributors to cardiovascular risk. Such approaches may enable phenotype-specific strategies to better understand and ultimately mitigate the brain-heart consequences of epilepsy.