Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease
- 1Baylor College of Medicine
Abstract
Background: The development of {beta}-amyloid (A{beta}) 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 A{beta} phagocytosis. Astrocytic, but not endothelial, disruption of sEH recapitulated the reductions in A{beta} 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 A{beta} clearance, highlighting sEH inhibition as a therapeutic strategy targeting both neuroinflammation and lysosomal dysfunction in AD.
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BibTeX
@misc{ghosh2026astrocytic,
title = {{Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease}},
author = {B. Ghosh and S. Wang and C. Qi and A. Ghosh and M. Comerota and C. S. Rajpurohit and D. C. Zeldin and H. Zheng},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759679},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759679v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease
AU - B. Ghosh
AU - S. Wang
AU - C. Qi
AU - A. Ghosh
AU - M. Comerota
AU - C. S. Rajpurohit
AU - D. C. Zeldin
AU - H. Zheng
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759679
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759679v1
AB - Background: The development of {beta}-amyloid (A{beta}) 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 A{beta} phagocytosis. Astrocytic, but not endothelial, disruption of sEH recapitulated the reductions in A{beta} 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 A{beta} clearance, highlighting sEH inhibition as a therapeutic strategy targeting both neuroinflammation and lysosomal dysfunction in AD.
ER -