Joshi, Radhika; Brezani, Veronika; Mey, Gabrielle M; Guixé-Muntet, Sergi; Ortega-Ribera, Marti; Zhuang, Yuan; Zivny, Adam; Werneburg, Sebastian; Jordi-Sancho, Gracia; Szabo, Gyongyi (12 March 2024). IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease. 10.1101/2024.03.08.582968
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2024.03.08.582968v1.full.pdf - Published Version Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND). Download (2MB) | Preview |
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.
Item Type: |
Working Paper |
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Division/Institute: |
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine |
UniBE Contributor: |
Jordi, Gracia |
Subjects: |
600 Technology > 610 Medicine & health |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
02 May 2024 10:36 |
Last Modified: |
02 May 2024 10:46 |
Publisher DOI: |
10.1101/2024.03.08.582968 |
PubMed ID: |
38654824 |
Uncontrolled Keywords: |
ARM Activated response microglia Alzheimer’s disease DAM IRF3 IRM Interferon response microglia Neuroinflammation Type 1 interferon ZBP1 |
BORIS DOI: |
10.48350/196373 |
URI: |
https://boris.unibe.ch/id/eprint/196373 |
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