Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation

Sci Rep. 2020 Jul 1;10(1):10755. doi: 10.1038/s41598-020-67549-7.

Abstract

Nurr1, a transcription factor belonging to the orphan nuclear receptor, has an essential role in the generation and maintenance of dopaminergic neurons and is important in the pathogenesis of Parkinson' disease (PD). In addition, Nurr1 has a non-neuronal function, and it is especially well known that Nurr1 has an anti-inflammatory function in the Parkinson's disease model. However, the molecular mechanisms of Nurr1 have not been elucidated. In this study, we describe a novel mechanism of Nurr1 function. To provide new insights into the molecular mechanisms of Nurr1 in the inflammatory response, we performed Chromatin immunoprecipitation sequencing (ChIP-Seq) on LPS-induced inflammation in BV2 cells and finally identified the RasGRP1 gene as a novel target of Nurr1. Here, we show that Nurr1 directly binds to the RasGRP1 intron to regulate its expression. Moreover, we also identified that RasGRP1 regulates the Ras-Raf-MEK-ERK signaling cascade in LPS-induced inflammation signaling. Finally, we conclude that RasGRP1 is a novel regulator of Nurr1's mediated inflammation signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chromatin / chemistry
  • DNA-Binding Proteins / metabolism*
  • Dopaminergic Neurons / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Inflammation / metabolism*
  • Introns
  • Lipopolysaccharides / chemistry
  • Mice
  • Microglia / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
  • Parkinson Disease / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Lipopolysaccharides
  • NR4A2 protein, human
  • Nr4a2 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • RASGRP1 protein, human
  • Rasgrp1 protein, mouse
  • Transcription Factors