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

Mihee Oh,Sun Young Kim,Woonghee Lee,Bonsu Ku,Baek-Soo Han,Won-Kon Kim,Jung-Eun Gil,Kwang-Hee Bae,Eun-Woo Lee,Sang Chul Lee,Kyoung-Jin Oh,Dong-Wook Cha,Jeong-Su Byun

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.

Highlights

Nurr[1], 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)
Nurr[1] functions as a key component of a negative feedback loop in both microglia and astrocytes by recruiting CoREST corepressor complexes to NF-κB target g enes[12]. They found that a reduction of Nurr[1] expression in itself does not affect the death of T H+ dopaminergic neurons, but the expression of inflammatory mediators are enhanced, and the survival rate of TH+ neurons are decreased in response to inflammatory stimuli in the Nurr[1] deficiency condition[12]
Because it was reported that Nurr[1] has an important role in inflammation in microglia and astrocytes, we investigated the effects of the over-expressed Nurr[1] on the expression of proinflammatory cytokine genes in BV2 cells

Summary

Introduction

Nurr[1], 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). Nurr[1] functions as a key component of a negative feedback loop in both microglia and astrocytes by recruiting CoREST corepressor complexes to NF-κB target g enes[12] They found that a reduction of Nurr[1] expression in itself does not affect the death of T H+ dopaminergic neurons, but the expression of inflammatory mediators are enhanced, and the survival rate of TH+ neurons are decreased in response to inflammatory stimuli in the Nurr[1] deficiency condition[12]. They suggested that these toxic mediators have an additive or synergistic effect with neurotoxic factors produced by microglia and lead to damaged dopaminergic neurons[12,13,14,15] Based on these results, they proposed that Nurr[1] suppresses the production of the microglia-derived pro-inflammatory mediators in response to inflammatory stimuli, and the toxic signal is not delivered to astrocytes. They mentioned that lower levels of NURR1 gene expression is significantly associated with an increased risk of PD in males and older subjects, r espectively[20]

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