Age-Related Features of Neuroinflammation: Hidden Association of Neuronal Damage with Activation of Natural Killers in Patients with Ischemic Stroke

Ischemic stroke remains a leading cause of death and disability worldwide, with neuroinflammation playing a central role in its pathogenesis. This study aimed to investigate age-related differences in neuroinflammatory responses in the human cerebral cortex following ischemic stroke. Using autopsy-derived brain tissue from 184 patients histological, histochemical, multiplex immunofluorescence, ELISA, and qRT-PCR analyses were conducted to assess neuronal damage, immune cell infiltration and cytokine expression. Morphological examination revealed pannecrosis in infarct cores and moderate inflammatory infiltration in penumbral regions. Multiplex immunofluorescence demonstrated active migration of NK (CD45+CD56+CD3−) and NKT (CD45+CD56+CD3+) cells in young patients, whereas elderly individuals showed a predominance of T lymphocytes (CD45+CD56−CD3+) and a decline in NK/NKT activity. Molecular assays indicated elevated NKG2D receptor expression and higher IFN-γ and proinflammatory cytokine (TNF-α, IL-1β, IL-6) levels in young patients, contrasting with dysregulated cytokine balance and reduced NK cytotoxicity in the elderly. These findings highlight distinct age-dependent immune mechanisms underlying ischemic injury, demonstrating that NK and NKT cells play a crucial role in early neuroinflammation, while aging shifts the balance toward adaptive immune dominance. The study underscores the need to consider patient age when designing neuroprotective and anti-inflammatory therapeutic strategies for ischemic stroke. © 2025 by the authors.