Astrocytic sEH–EET signaling regulates microglial lysosomal function and suppresses the STING–Type I interferon pathway in Alzheimer’s disease
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Background
The development of β-amyloid (Aβ) pathology in Alzheimer’s disease (AD) is accompanied by profound changes in astrocytes and microglia and associated neuroinflammation. Soluble epoxide hydrolase (sEH), which degrades anti-inflammatory epoxyeicosatrienoic acids (EETs), is elevated in the AD brain, yet how EETs restrain inflammation remains poorly understood.
Methods
We performed single-nucleus RNA sequencing (snRNA-seq) on brains from wild-type, sEH knockout, 5xFAD, and 5xFAD; sEH knockout mice, and used primary mouse microglia and human induced pluripotent stem cell (iPSC)-derived microglia to define the underlying mechanism. To test cell-type-specific contributions, we generated astrocyte- and endothelial-specific she knockout mice and crossed them with 5xFAD mice.
Results
Genetic disruption of sEH in 5xFAD mice markedly reduced the abundance of a type I interferon (IFN)-responsive microglial subcluster and lowered phospho-STING (pSTING) levels. In primary microglia, supplementation with 11,12-EET attenuated STING activation and IFN target gene expression; blocking lysosomal acidification abolished this effect and caused pSTING to accumulate, identifying lysosomal degradation as a critical route for terminating STING signaling. 11,12-EET also enhanced microglial lysosomal acidification and Aβ phagocytosis. Astrocytic, but not endothelial, disruption of sEH recapitulated the reductions in Aβ pathology and microglial STING activation seen in global sEH-deficient mice, identifying astrocytes as the major cellular source of EETs regulating this pathway.
Conclusion
We define an astrocyte–microglia axis in which astrocytic sEH limits EET availability and thereby sustains microglial STING signaling. By promoting lysosomal clearance of pSTING, EETs suppress type I IFN signaling and enhance microglial Aβ clearance, highlighting sEH inhibition as a therapeutic strategy targeting both neuroinflammation and lysosomal dysfunction in AD.
