Abstract DP219: Brain–Thymus–Immune Aging Axis in Stroke: Novel Insights From a Photothrombotic Thymic Ischemia Model

Background: Aging is a major comorbidity of ischemic stroke (IS), and the thymus—central to T-cell development—plays a pivotal role in immune regulation. While age-related thymic atrophy is well described, whether acute thymic ischemia after stroke drives post-stroke immunosenescence remains unknown. The impact of isolated thymic injury on brain function has never been systematically examined. We aimed to characterize thymic structural and functional changes after IS and established a novel photothrombotic thymic ischemia (TI) model to directly investigate brain–thymus–immune aging interactions. Methods: Male C57BL/6J mice (6–8 months) underwent photothrombotic middle cerebral artery occlusion (pMCAO) or TI. Neurological recovery and cognition were assessed over 28 days. Thymic architecture, T-cell maturation (flow cytometry), lipid deposition, and cellular senescence were evaluated by histology, Oil Red O, and SA-β-gal staining. RNA sequencing with Gene Ontology (GO) analysis identified ischemia-related pathways. Results: After pMCAO, thymuses showed cortical–medullary disruption, vacuolated stromal cells, reduced thymic index, and loss of cellularity by day 14. DP and DN thymocytes were markedly altered, with skewed SP CD4/CD8 maturation. RNA-seq revealed downregulation of lipid metabolism genes (Abca1, Apoa1, Scd1) and keratin family genes linked to thymic aging, impairing cholesterol clearance and promoting adipogenesis. In the TI model, acute-phase changes mirrored post-stroke thymic injury, with persistent DN subset abnormalities and incomplete functional recovery at day 28. TI upregulated collagen and chemokine genes (Col1a1, Ccl7, Ccl12), enriched for cytokine-mediated signaling and collagen fibril organization, suggesting epithelial–mesenchymal transition–driven fibrosis and senescence. Lipid droplet accumulation and SA-β-gal positivity confirmed accelerated immunosenescence. Strikingly, TI alone induced long-term cognitive deficits and amplified post-stroke-like neuroinflammation, with M1 microglial activation and astrocytic GFAP upregulation. Conclusion: We demonstrate for the first time that acute thymic ischemia—secondary to stroke or isolated—disrupts T-cell maturation, accelerates immunosenescence, and aggravates cognitive decline. Our novel TI model uncovers a previously unrecognized brain–thymus–immune aging axis in stroke, identifying thymic preservation and immune modulation as promising therapeutic strategies to enhance recovery.