Joshi, RadhikaRadhikaJoshiBrezani, VeronikaVeronikaBrezaniMey, Gabrielle MGabrielle MMeyGuixé-Muntet, SergiSergiGuixé-MuntetOrtega-Ribera, MartiMartiOrtega-RiberaZhuang, YuanYuanZhuangZivny, AdamAdamZivnyWerneburg, SebastianSebastianWerneburgGracia-Sancho, JordiJordiGracia-SanchoSzabo, GyongyiGyongyiSzabo2024-10-262024-10-262024-03-12https://boris-portal.unibe.ch/handle/20.500.12422/177087The 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.enARM Activated response microglia Alzheimer’s disease DAM IRF3 IRM Interferon response microglia Neuroinflammation Type 1 interferon ZBP1600 - Technology::610 - Medicine & healthworking_paper10.48350/1963733865482410.1101/2024.03.08.582968