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bioRxiv · 10.1101/2024.03.08.582968

IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.

Szabo, G.·Joshi, R.·Brezani, V.·Mey, G. M.·Guixe-Muntet, S.·Ortega-Ribera, M.·Zhuang, Y.·Zivny, A.·Werneburg, S.·Gracia-Sancho, J.
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Abstract

The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D:IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimers Disease, notably apolipoprotein-e. Lastly, using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 as a target of IRF3 that is relevant across various neuroinflammatory disorders. Together, our results identify IRF3 as an important regulator of LPS-mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.

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Szabo, G., Joshi, R., Brezani, V., Mey, G. M., Guixe-Muntet, S., Ortega-Ribera, M., Zhuang, Y., Zivny, A., Werneburg, S., Gracia-Sancho, J.. 2024-03-13. IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.. https://doi.org/10.1101/2024.03.08.582968

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