AAV-mediated inhibition of endothelial IL-1β/IL-1R1 signaling alleviates the development of sepsis-associated encephalopathy.

Sepsis-Associated Encephalopathy (SAE), a disorder affecting the central nervous system (CNS), is highly prevalent, occurring in approximately 70 % of sepsis patients in intensive care units (ICU). Although numerous studies have highlighted the critical role of IL-1β in the pathogenesis of SAE, the specific downstream mechanisms remain poorly understood. Moreover, the Phase III clinical trial of IL-1R1 antagonists for SAE therapy ended in failure. In this study, we found that IL-1R1, the receptor for IL-1β, is exclusively and highly expressed on CNS endothelial cells during early sepsis. Specifically inhibiting IL-1R1 expression in endothelial cells during the early stage of sepsis can significantly suppress the onset of SAE. Mechanistically, elevated levels of LPS, IL-1α, or IL-1β in the serum during sepsis induce IL-1R1 expression on endothelial cells, leading to the activation of IL-1β signaling. Activation of the IL-1β/IL-1R1 signaling pathway in endothelial cells triggers the expression of adhesion molecules, pro-inflammatory cytokines, and chemokines, which in turn exacerbate neuroinflammation and contribute to cognitive impairments. This research not only elucidates the pathogenic mechanisms underlying SAE but also introduces an advanced approach for targeted gene intervention in CNS endothelial cells, potentially offering a new strategy for the treatment of SAE and other neurodegenerative disease induced by systemic inflammation.