NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models

• Published in: Journal of neuroinflammation 2023-04, Vol.20 (1), p.96-96, Article 96
• Main Authors: Liu, Zhaolin, Shen, Chenye, Li, Heng, Tong, Jiabin, Wu, Yufei, Ma, Yuanyuan, Wang, Jinghui, Wang, Zishan, Li, Qing, Zhang, Xiaoshuang, Dong, Hongtian, Yang, Yufang, Yu, Mei, Wang, Jian, Zhou, Renyuan, Fei, Jian, Huang, Fang
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology; AKT protein; Analysis; Animals; Antibodies; Astrocytes; Care and treatment; Caspase; Cell activation; Chromatography; Cyclooxygenase-2; Diabetes; Disease Models, Animal; Dopamine - metabolism; Dopamine receptors; Dopaminergic Neurons - metabolism; Gene expression; Glial cells; Glycogen Synthase Kinase 3 beta; Inflammation; Infrared imaging systems; Interleukin 6; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Laboratories; Lipopolysaccharides; Lipopolysaccharides - metabolism; MAP kinase; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Microscopy; Movement disorders; MPP; MPTP; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neuroinflammation; Neuroinflammatory Diseases; Neuronal survival; Neuronal-glial interactions; Neurotoxicity; NF-kappa B - metabolism; NF-κB protein; NLR Proteins - metabolism; NLRC5; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Prevention; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Risk factors; Signal transduction
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02755-4

Parkinson's disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1β, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT-GSK-3β and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.