CCAAT/Enhancer-binding protein β promotes pathogenesis of EAE.
CCAAT/Enhancer-binding protein β promotes pathogenesis of EAE.
复制标题
DOI：
10.1016/j.cyto.2017.01.005
复制
发表时间：
2017-04
期刊：
影响因子：
3.8
通讯作者：
McGeachy MJ
中科院分区：
文献类型：
--
作者：
Simpson-Abelson MR;Hernandez-Mir G;Childs EE;Cruz JA;Poholek AC;Chattopadhyay A;Gaffen SL;McGeachy MJ
CCAAT/增强子结合蛋白β（C/EBPβ）转录因子可被多种炎症刺激物（包括IL-17和LPS）激活，C/EBPβ本身可调节许多参与炎症的基因。然而，C/EBPβ在驱动自身免疫中的作用还不清楚。在这里，我们证明了Cebpb−/−小鼠对EAE具有抗性。Cebpb−/−小鼠在EAE诱导后表现出减少的淋巴细胞和APC向CNS的浸润。此外，MOG诱导的Th 17细胞因子的产生在引流LN中受损，表明Th 17细胞引发缺陷。体外Th 17极化研究表明，T细胞应答并非固有缺陷，而是支持C/EBPβ在髓系细胞活化中的已知作用，作为体内缺陷性Th 17引发的可能机制。然而，我们确实发现了C/EBPβ在调节APC中ll 23 r表达中的意想不到的作用。ChIP检测证实C/EBPβ可直接与树突状细胞和Th 17细胞中的IL 23 r基因启动子结合。这些数据确立了C/EBPβ作为EAE中自身免疫性炎症的关键驱动因素，并提出了C/EBPβ在调节IL-23 R表达中的新作用。
The CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor is activated by multiple inflammatory stimuli, including IL-17 and LPS, and C/EBPβ itself regulates numerous genes involved in inflammation. However, the role of C/EBPβ in driving autoimmunity is not well understood. Here, we demonstrate that Cebpb−/− mice are resistant to EAE. Cebpb−/− mice exhibited reduced lymphocyte and APC infiltration into CNS following EAE induction. Furthermore, MOG-induced Th17 cytokine production was impaired in draining LN, indicating defects in Th17 cell priming. In vitro Th17 polarization studies indicated that T cell responses are not inherently defective, instead supporting the known roles for C/EBPβ in myeloid lineage cell activation as the likely mechanism for defective Th17 priming in vivo. However, we did uncover an unexpected role for C/EBPβ in regulating ll23r expression in APCs. ChIP assays confirmed that C/EBPβ binds directly to the Il23r gene promoter in dendritic cells and Th17 cells. These data establish C/EBPβ as a key driver of autoimmune inflammation in EAE, and propose a novel role for C/EBPβ in regulation of IL-23R expression.