Endothelial Type I Interferon signaling modulates the vascular response to ischemic brain injury

Tuohy, M. C.; Kuo, P.-C.; Chelminski, A.; Muharremi, E.; DeSantis, C.; Cui, A.; Russo, A.; Jamoul, D.; Hillman, E.; Crary, J. F.; Yen, J.-H. J.; Agalliu, D.

doi:10.1101/2025.09.09.675258

bioRxiv · 10.1101/2025.09.09.675258

Endothelial Type I Interferon signaling modulates the vascular response to ischemic brain injury

Tuohy, M. C.·Kuo, P.-C.·Chelminski, A.·Muharremi, E.·DeSantis, C.·Cui, A.·Russo, A.·Jamoul, D.·Hillman, E.·Crary, J. F.·Yen, J.-H. J.·Agalliu, D.

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Abstract

Vascular normalization [stabilization of aberrant angiogenesis and restoration of blood-brain barrier (BBB)] is critical for reducing long-term secondary sequelae after ischemic stroke. How immune and developmental signaling pathways coordinate these processes is poorly understood. Here we identify a unique brain endothelial cell (BEC) type one interferon (IFN1) signature in human and mouse ischemic stroke tissue. By leveraging two clinically-relevant murine ischemic stroke models, single-cell transcriptomics, and BBB functional assays, we find that deletion of endothelial IFN1 receptor (Ifnar1) exacerbates post-stroke BBB disruption and expands a BEC population expressing angiogenic and immature BBB markers. Conversely, IFN{beta} administration after stroke reduces acute BBB disruption. Activation of IFN1 signaling in BECs in vitro reduces vascular endothelial growth factor (VEGF) signaling to promote junctional stabilization, enhance barrier properties, and suppress angiogenic features. Thus, endogenous endothelial IFN1 signaling modulates BBB dysfunction and angiogenesis to promote vascular normalization after ischemic brain injury.

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Tuohy, M. C., Kuo, P.-C., Chelminski, A., Muharremi, E., DeSantis, C., Cui, A., Russo, A., Jamoul, D., Hillman, E., Crary, J. F., Yen, J.-H. J., Agalliu, D.. 2025-09-17. Endothelial Type I Interferon signaling modulates the vascular response to ischemic brain injury. https://doi.org/10.1101/2025.09.09.675258

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