Nur77 attenuates inflammatory responses and oxidative stress by inhibiting phosphorylated IκB-α in Parkinson's disease cell model.

Junqiang Yan,Liang Qiao,Hua Fan,Jiarui Huang,Xiaoyi Lai,Mengmeng Shen,Jiannan Wu,Anran Liu

doi:10.18632/aging.103128

Abstract

Neuroinflammation and oxidative stress play key roles in the pathological development of Parkinson’s disease (PD). Nerve growth factor-induced gene B (Nur77) is closely related to dopamine neurotransmission, and its pathogenesis is unclear. This study aims to investigate the role and mechanism of Nur77 in a cell model of Parkinson’s disease. Silencing Nur77 with siRNA can aggravate intracellular LDH release, increase the expression of pro-inflammatory genes (such as tumor necrosis factor α, nuclear factor κB (p65), monocyte chemotactic protein 1, interleukin-6), and decrease cell survival, decrease expression of nuclear factor E2-related factor(Nrf2), heme oxygenase 1, NADPH quinineoxidoreductase-1. Cytosporone B (Nur77 agonist) has the opposite effect to Nur77 silencing. PDTC (NF-κB inhibitor / antioxidant) can also inhibit pro-inflammatory genes to a similar degree as Cytosporone B. Phosphorylated IκB-α can be inhibited by Cytosporone B, while silencing Nur77 can increase the protein expression level of phosphorylated IκB-α. After silencing IκB-α, both Cytosporone B and siNur77 did not affect pro-inflammatory genes and antioxidant stress. These findings reveal the first evidence that Nur77 exerts anti-inflammatory and antioxidant stress effects by inhibiting IκB-α phosphorylation expression in a Parkinson cell model. Nur77 may be a potential therapeutic target for Parkinson’s disease.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD)
MPP+-treated significantly increased the level of tumor necrosis factor-α (TNF-α), MCP-1 and IL-6 of PC12 cells, but CSN-B could reduce the expressive level of TNF-α, MCP-1 and IL-6, which demonstrated that CSN-B can inhibit inflammatory response
Our study showed that CSN-B can upregulate Nrf2, HO-1, NQO-1 and exert anti-oxidative stress response, while silencing of Nur77 with small interfering RNAs (siRNAs) increased the protein expression levels of TNF-α, MCP1, IL-6 and decreased Nrf2, HO-1, NQO-1 in MPP+lesioned PC12 cells

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD). The underlying cause of dopaminergic neurodegeneration remains unclear, neuroinflammatory responses contribute to the pathogenesis of PD. Increasing evidence suggests that Nur plays a very important role in PD [4]. Nur is a member of the NR4A subfamily of nuclear receptors and plays a very important role in many biological processes. Nur can reduce inflammatory responses through direct interactions with the p65 component of nuclear factor κB(NF-κB) [12]. Nur knockout mice significantly www.aging-us.com enhanced inflammatory responses characterized by a marked increase in IκB-α (NF-κB inhibitory protein) phosphorylation [13], which corresponds to elevated NF-κB activity. Nur plays an anti-inflammatory role by activating macrophages [14]. Nur expression has been detected in peripheral eosinophils from patients with atopic dermatitis [15]

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