NR1H4 ameliorates Parkinson’s disease via inhibiting astrocyte activation and neuroinflammation in a CEBPβ/NF-κB dependent manner
Jingwen Li, Hanshu Liu, Xinyu Hu, Shurui Zhang, Qinwei Yu, Guiying Kuang, Long Liu, Danfang Yu, Jinsha Huang, Yun Xia, Tao Wang, Nian Xiong
Abstract
• We provided the evidence that NR1H4 expressed in astrocytes and extremely down-regulated during PD progression. • NR1H4 protected against PD by suppressing astrocyte activation, neuroinflammation and ROS damage. • RNA-seq and ChIP-qPCR results suggested Nr1h4 manipulated the inflammation in astrocytes via CEBPβ/NF-κB pathway. • In vitro and in vivo experiments proved that pharmacologic activation of NR1H4 by Obeticholic acid alleviated the inflammation and ROS damage . Parkinson’s Disease (PD) is a degenerative disease driven by neuroinflammation. Nuclear receptor subfamily 1 group H member 4 (NR1H4), a nuclear receptor involved in metabolic and inflammatory regulation, is found to be widely expressed in central nervous system. Previous studies suggested the protective role of NR1H4 in various diseases related to inflammation, whether NR1H4 participates in PD progression remains unknown. To investigate the role of NR1H4 in neuroinflammation regulation, especially astrocyte activation during PD, siRNA and adenovirus were used to manipulate Nr1h4 expression. RNA-sequencing (RNA-seq), quantitative real-time PCR, enzyme-linked immunosorbent assay, Chromatin immunoprecipitation and western blotting were performed to further study the underlying mechanisms. We identified that NR1H4 was down-regulated during PD progression. In vitro experiments suggested that Nr1h4 knockdown led to inflammatory response, reactive oxygen species generation and astrocytes activation whereas Nr1h4 overexpression had the opposite effects. The results of RNA-seq on astrocytes revealed that NR1H4 manipulated neuroinflammation in a CEBPβ/NF-κB dependent manner. Additionally, pharmacological activation of NR1H4 via Obeticholic acid ameliorated neuroinflammation and promoted neuronal survival. Our study first proved the neuroprotective effects of NR1H4 against PD via inhibiting astrocyte activation and neuroinflammation in a CEBPβ/NF-κB dependent manner.