Neuroinflammation and Alzheimer’s disease
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 Aβ in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Aβ -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.
Selected Publications
Joshi, R., Brezani, V., Mey, G.M. et al. IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer’s disease. J Neuroinflammation 21, 212 (2024). https://doi.org/10.1186/s12974-024-03203-7.
Zhuang Y, Ortega-Ribera M, Nagesh PT, Joshi R, Huang H, Wang Y, Zivny A, Mehta J, Parikh SM, Szabo G. Bile acid-induced IRF3 phosphorylation mediates cell death, inflammatory responses, and fibrosis in cholestasis-induced liver and kidney injury via regulation of ZBP1. Hepatology (Baltimore, Md.). 2024;79(4):752–767.
Ortega-Ribera M, Zhuang Y, Brezani V, Nagesh PT, Joshi RS, Babuta M, Wang Y, Szabo G. G-CSF increases calprotectin expression, liver damage and neuroinflammation in a murine model of alcohol-induced ACLF. Frontiers in cell and developmental biology. 2024;12:1347395.
Ramos A, Joshi RS, Szabo G. Innate immune activation: Parallels in alcohol use disorder and Alzheimer’s disease. Frontiers in molecular neuroscience. 2022;15:910298.