The mechanisms by which hypothalamic neuroinflammation induced by neonatal cerebral ischemia-hypoxia leads to decreased thymic function via the HPA axis.

Hypoxic-ischemic encephalopathy (HIE) represents the leading cause of acute neonatal mortality and chronic neurological disorders. The impact of HIE on neonatal immune system development and the underlying mechanisms remain unclear. In this study, we employed the Sprague-Dawley neonatal rat hypoxic-ischemic (HI) model to investigated how HIE affected thymus and hypothalamic-pituitary-adrenal (HPA) axis, and to explore the mechanisms underlying their interaction. Our findings indicate that HI induced atrophy, elevated protein levels associated with apoptosis and autophagy, and reduced thymic lymphocyte counts in neonatal rats. Concurrently, HI suppressed activation of the PI3K/Akt/mTOR signaling pathway in thymus. Furthermore, HI significantly increased levels of inflammatory cytokines, activated microglia, and stimulated the HMGB1/TLR4/NF-κB signaling pathway in hypothalamus. HI also led to hyperactivation of the HPA axis. Conversely, treatment with the glucocorticoid receptor antagonist (RU486) or the HMGB1 inhibitor markedly attenuated these effects. These results suggest that HI may trigger neuroinflammation via activation of HMGB1/TLR4/NF-κB signaling pathway in hypothalamic microglia, which subsequently hyperactivates the HPA axis, thereby promoting thymic apoptosis and autophagy, impairing thymic development in neonatal rat, and ultimately contributing to systemic immunosuppression.