| First Author | Joshi R | Year | 2024 |
| Journal | J Neuroinflammation | Volume | 21 |
| Issue | 1 | Pages | 212 |
| PubMed ID | 39215356 | Mgi Jnum | J:353898 |
| Mgi Id | MGI:7715873 | Doi | 10.1186/s12974-024-03203-7 |
| Citation | Joshi R, et al. (2024) IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease. J Neuroinflammation 21(1):212 |
| abstractText | 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. Using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 (ZBP1) as a target of IRF3 that is relevant across various neuroinflammatory disorders. Lastly, we show IRF3 phosphorylation and IRF3-dependent ZBP1 induction in response to Abeta in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Abeta -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases. |
