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

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 LPSinduced inflammation signaling. Finally, we conclude that RasGRP1 is a novel regulator of Nurr1's mediated inflammation signaling. Nurr1 (NR4A2) belongs to the nuclear receptor (NR)4 family of orphan nuclear receptors 1. NRs are ligand inducible transcription factors that bind to DNA and regulate the expression of target genes 2. Developing mesencephalic dopaminergic cells deficient in Nurr1 are unable to express tyrosine hydroxylase 3,4. Nurr1 deficiency in embryonic ventral midbrain cells causes them not to migrate normally, and they fail to innervate their striatal target areas 5. It has been suggested that the absence of Nurr1 may be a contributing factor in the pathogenesis of PD 6. Recently, two human mutations located in exon 1 of the Nurr1 gene were shown to result in a decreased expression of Nurr1 mRNA and were associated with familial PD 7. Additionally, recent studies have proposed that Nurr1 overexpression or modification of Nurr1 expression in stem cells (and neural stem cells) may have an impact on the future of cell therapy for PD 8-11. It is further supported by a link between altered Nurr1 expression and PD indicating that Nurr1 may have a protection role. Saijo et al. reported that Nurr1 protects dopaminergic neurons from inflammation-induced neurotoxicity through the inhibition of pro-inflammatory mediator expression in microglia and astrocytes 12. Nurr1 functions as a key component of a negative feedback loop in both microglia and astrocytes by recruiting CoREST corepressor complexes to NF-κB target genes 12. They found that a reduction of Nurr1 expression in itself does not affect the death of TH + 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 Nurr1 deficiency condition 12. Moreover, they mentioned that astrocytes can act as amplifying agents of microglia-derived proinflammatory mediators in the production of neurotoxic factors 12-14. Collectively, the expression of LPS-induced pro-inflammatory genes in microglia lead to...

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“…Interaction of Nurr1 with NF‐κB p65 was also shown to inhibit α‐synuclein‐induced TNF‐α production in BV‐2 cells 122 . A recent study using BV‐2 cells proved another mechanism of the action, in that Nurr1 directly bound to the RasGRP1 intron to reduce its expression, thereby inhibited the recruitment of Raf/MEK/ERK signaling and inflammatory cytokine production 123 . The regulatory roles of Nurr1 in microglia‐mediated inflammation in vivo have been demonstrated by the findings that short hairpin RNA‐mediated knockdown or conditional knockout of Nurr1 exacerbated the inflammatory pathology and the degeneration of dopaminergic neurons in the substantia nigra 121,124 .…”

Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets

“…The mechanism operates well in microglia (brain macrophages) and astrocytes, and is important for protecting dopaminergic neurons from death [208] . Nurr1 also binds to the Ras guanyl-releasing protein 1 (RasGRP1) intron to regulate its expression [209] . RasGRP1 regulates the Ras-Raf-MEK-ERK signaling cascade downstream to TLR4 signaling [209] .…”

“…Nurr1 also binds to the Ras guanyl-releasing protein 1 (RasGRP1) intron to regulate its expression [209] . RasGRP1 regulates the Ras-Raf-MEK-ERK signaling cascade downstream to TLR4 signaling [209] . The binding of prostaglandin E1 (PGE1) and PGA2 to the Nurr1 or NR4A2 enhances its anti-inflammatory action [210] .…”