Activation of Nur77 in microglia attenuates proinflammatory mediators production and protects dopaminergic neurons from inflammation‐induced cell death

• Published in: Journal of neurochemistry 2017-02, Vol.140 (4), p.589-604
• Main Authors: Liu, Tian‐Ya, Yang, Xiao‐Ying, Zheng, Long‐Tai, Wang, Guang‐Hui, Zhen, Xue‐Chu
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Apoptosis; Attenuation; Cell death; Cell Death - physiology; Cells, Cultured; Cyclooxygenase-2; Cytotoxicity; Data processing; Dopamine; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Inflammation; Inflammation - metabolism; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Inhibition; Interleukin 1; Lipopolysaccharides; Male; MAP kinase; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Microglia - pathology; Movement disorders; MPTP; MPTP Poisoning - metabolism; Neurochemistry; Neurodegenerative diseases; neuroinflammation; Neuromodulation; Neurons; Neurotoxicity; NF-κB protein; NF‐κB; Nitric oxide; Nitric-oxide synthase; Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism; Nur77; Nur77 protein; Overexpression; p38 mitogen‐activated protein kinase; Parkinson's disease; Rodents; Substantia nigra
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13907

Microglia‐mediated neuroinflammation plays a critical role in the pathological development of Parkinson's disease (PD). Orphan nuclear receptor Nur77 (Nur77) is abundant in neurons, while its role in microglia‐mediated neuroinflammation remains unclear. The present data demonstrated that the expression of Nur77 in microglia was reduced accompanied by microglia activation in response to lipopolysaccharide (LPS) in vitro and in experimental 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐PD mouse model. Nur77 over‐expression or application of Nur77 agonist cytosporone B suppressed the expression of proinflammatory genes, such as inducible nitric oxide NOS, cyclooxygenase‐2, IL‐1β, and tumor necrosis factor‐α in the activated microglia, while silenced Nur77 exaggerated the inflammatory responses in microglia. Moreover, activation of Nur77 suppressed the LPS‐induced NF‐κB activation which was partly dependent on p38 MAPK activity, since inhibition of p38 MAPK by SB203580 abolished the LPS‐activated NF‐κB in microglia. On the other hand, inhibition of p38 MAPK attenuated LPS‐induced Nur77 reduction. Furthermore, in a microglia‐conditioned cultured media system, Nur77 ameliorated the cytotoxicity to MN9D dopaminergic cells. Lastly, cytosporone B attenuated microglia activation and loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc) of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐PD mouse model. Taken together, these findings revealed the first evidence that Nur77 was an important modulator in microglia function that associated with microglia‐mediated dopaminergic neurotoxicity, and thus modulation of Nur77 may represent a potential novel target for treatment for neurodegenerative disease. The orphan nuclear receptor Nur77 is abundant in neurons, while its role in microglia‐mediated neuroinflammation – which play a critical role in the pathological development of Parkinson's diease, remains unclear. In vitro and in vivo experiments demonstrated that Nur77 was reduced in activated microglia, and functioned as a negative regulator on the production of proinflammatory factors. We also discovered that Nur77 suppressed microglia activation mainly through suppressing p38 mitogen‐activated protein kinase (p38 MAPK) and nuclear factor‐κB (NF‐κB) activation and protected dopaminergic neurons from inflammation‐induced death.