Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, USA.
Department of Opthalmology and Visual Sciences, Kellogg Eye Center Michigan Neuroscience Institute, University of Michigan, Ann Arbor, USA.
J Neuroinflammation. 2024 Aug 30;21(1):212. doi: 10.1186/s12974-024-03203-7.
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.
干扰素信号的病理作用在神经炎症性疾病中逐渐显现，但干扰素调节因子 3（IRF3）在神经炎症中的具体作用仍知之甚少。在这里，我们表明，全局 IRF3 缺陷会延迟 TLR4 介导的小胶质细胞信号转导，并减弱 LPS 诱导的炎症的标志性特征，如细胞因子释放、小胶质细胞反应性、星形胶质细胞激活、髓样细胞浸润和炎性体激活。此外，小胶质细胞中组成型激活的 IRF3（S388D/S390D：IRF3-2D）的表达会诱导类似于活化反应性小胶质细胞的转录程序，并表达与阿尔茨海默病相关的基因，特别是载脂蛋白 E。使用 IRF3-2D 脑髓样细胞的批量 RNA-seq，我们确定 Z-DNA 结合蛋白-1（ZBP1）是 IRF3 的一个靶标，在各种神经炎症性疾病中都具有相关性。最后，我们证明了在原代小胶质细胞培养物中，Aβ 会引起 IRF3 磷酸化和 IRF3 依赖性 ZBP1 诱导。综上所述，我们的研究结果表明，IRF3 是 LPS 和 Aβ 介导的神经炎症反应的重要调节因子，并强调了 IRF3 作为不同神经炎症性疾病中特定疾病基因激活的中央调节因子的作用。
