Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS Scientific Institute San Raffaele, Milan, Italy.
Experimental Imaging Center, IRCCS Scientific Institute San Raffaele, Milan, Italy.
J Autoimmun. 2023 Jul;138:103053. doi: 10.1016/j.jaut.2023.103053. Epub 2023 May 24.
Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders.
肝细胞核因子 4α（HNF4α）是一种对于胚胎发育至关重要的转录因子（TF），最近的研究表明其可以调节炎症基因的表达。为了研究 HNF4α 在免疫中的功能，我们测量了 HNF4α 拮抗剂对体外和体内免疫细胞反应的影响。HNF4α 阻断减少了实验性多发性硬化症（MS）模型中的免疫激活和疾病严重程度。人类免疫转录组的网络生物学研究揭示了 HNF4α 与 SP1 和 c-myc 一起作为主 TF，调节所有 MS 阶段的差异表达。TF 表达受免疫细胞激活增强，受环境 MS 风险因素调节，并且在 MS 免疫细胞中比对照更高。针对 TF 表达或功能的化合物的给药在体外和体内证明了 CNS 自身免疫的非协同、相互依存的转录控制。总的来说，我们确定了一个核心调节转录网络，维持神经炎症，代表了治疗 MS 和其他炎症性疾病的有吸引力的治疗靶点。
