(1792) Gut-Derived γδT Cells and IL-17: Key Drivers of Sepsis-Associated Encephalopathy

Introduction: Sepsis-associated encephalopathy (SAE) significantly increases mortality among ICU patients. The gut, often termed the "engine" of sepsis and multiple organ dysfunction, plays a crucial role in this process. This study investigates whether a specific subset of small intestinal γδT cells migrates to the dura mater and secretes IL-17 following sepsis, contributing to microglial injury and exacerbating SAE.

Methods: We used Kaede mice to track cell migration and Cre/Floxp knockout mice to establish a cecal ligation and puncture (CLP) model of SAE. Mice were randomly assigned to 4 groups: Sham+ WT, sepsis (WT, TcrdCreERT2 IL7R flox/flox, TcrdCreERT2 CD8a flox/flox). Cognitive function was assessed 7d post-operation using the Morris water maze, Y-maze, and open field test. Transmission electron microscopy evaluated mitochondrial and synaptic damage, while Golgi staining assessed changes in neuronal dendrites. BV2 microglial cell lines, splenic γδT cells and primary microglial cells were co-cultured to validate pathway expression and cell damage. The injurious effects of IL-17 in SAE were confirmed by IL-17 AAV injection.

Results: γδT cells migrated from the small intestine to the dura mater, with IL-17 mainly secreted by the IL7Rhigh CD8alow subset. CLP+TcrdCreERT2 IL7R flox/flox mice exhibited less mitochondrial, synaptic, and dendritic spine damage in the hippocampus and improved cognitive function post-sepsis. LPS and IL-17 stimulation caused mitochondrial damage in BV2 cells and activated the cGAS-STING pathway. Transwell co-culture showed γδT cells exacerbated microglial damage under LPS stimulation, which was reversed by silencing IL-17A with siRNA. IL-17 AAV injection further damaged mitochondrial and synaptic structures in the hippocampus. CLP+TcrdCreERT2 IL7R flox/flox mice had reduced cGAS-STING expression and increased levels of synaptic proteins PSD95 and SYP.

Conclusions: Small intestinal γδT cells migrate to the dura mater following sepsis and secrete IL-17A, leading to mitochondrial damage in hippocampal microglia and activation of the cGAS-STING pathway, which exacerbates synaptic damage and SAE. This effect is primarily mediated by the IL7Rhigh CD8alow subset. These findings suggest a new potential target for SAE treatment and provide a foundation for future clinical research.