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Guixé-Muntet SAuthorGracia-Sancho JAuthor

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July 3, 2024
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IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease.

Publicated to:Biorxiv : The Preprint Server For Biology. - 2024-03-12 (), DOI: 10.1101/2024.03.08.582968

Authors: Joshi R; Brezani V; Mey GM; Guixé-Muntet S; Ortega-Ribera M; Zhuang Y; Zivny A; Werneburg S; Gracia-Sancho J; Szabo G

Affiliations

Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, USA. - Author
Department of Opthalmology and Visual Sciences, Kellogg Eye Center Michigan Neuroscience Institute, University of Michigan, Ann Arbor, USA. - Author
Liver Vascular Biology, IDIBAPS Biomedical Research Institute- CIBEREHD, Barcelona, Spain. - Author

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 Alzheimer's 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.

Keywords

Activated response microgliaAlzheimer’s diseaseArmDamInterferon response microgliaIrf3IrmNeuroinflammationType 1 interferonZbp1

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With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Israel; United States of America.