Central nervous system-derived inflammasome cytokines drive neuroglial injury and cerebral oedema in viral encephalitis, despite corticosteroid therapy

Herpes simplex virus (HSV) is the leading cause of encephalitis, with high rates of morbidity and mortality. Dysregulated immune responses have been associated with poor outcomes in small series, driving interest in immunotherapies. However, the key mediators of neuropathology, their cellular sources, and responsiveness to corticosteroid treatment remain unknown. We present findings from an RCT of dexamethasone in 55 adults with HSV encephalitis, alongside a representative murine model. Clinical severity and adverse outcomes were associated with neuroglial injury biomarkers (GFAP, tau, UCH-L1), increased cerebral oedema on MRI, and higher IL-1RA, IL-18, and IL-6. These mediators were more abundant in matched CSF than serum, and were not reduced by dexamethasone. In the model, neurons, astrocytes and microglia robustly expressed IL-1 and IL-6, supporting their CNS origin. These findings identify IL-1 and IL-6 signalling as key drivers of immunopathology in HSV encephalitis and potential therapeutic targets to mitigate neuroinflammation and improve outcomes. FundingNational Institute for Health and Care Research (grant number 12/205/28).