RIPK3 acts as a molecular switch between neuroprotection and neuropathology during herpes simplex encephalitis

Although inherited RIPK3 deficiency predisposes individuals to severe disease, how RIPK3 confers neuroprotection remains unclear. Using single-cell transcriptomics and genetic dissection, we show that RIPK3 acts as a molecular switch that balances antiviral defense with neuropathology in the central nervous system.

RIPK3 scaffolding activity drives type I interferon (IFN) production in neurons and coordinates type I and II IFN programs in astrocytes, microglia, and infiltrating myeloid cells, promoting immune differentiation and viral control. RIPK3-dependent apoptosis further limits myeloid accumulation and preserves neuronal homeostasis. In contrast, RIPK3 kinase activation in astrocytes triggers necroptosis, provoking neuronal loss, excessive myeloid infiltration, and lethal neuroinflammation.