CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling

• Published in: Brain (London, England : 1878) England : 1878), 2019-03, Vol.142 (3), p.700-718
• Main Authors: Meng, Fan, Guo, Zhige, Hu, Yaling, Mai, Weihao, Zhang, Zhenjie, Zhang, Bin, Ge, Qianqian, Lou, Huifang, Guo, Fang, Chen, Jiangfan, Duan, Shumin, Gao, Zhihua
• Format: Article
• Language: English
• Subjects: 5'-Nucleotidase - metabolism; 5'-Nucleotidase - physiology; Adenosine - metabolism; Adenosine - pharmacology; Adenosine - physiology; Animals; Disease Models, Animal; Dopamine - metabolism; Dopamine - physiology; Dopaminergic Neurons - metabolism; GPI-Linked Proteins - metabolism; GPI-Linked Proteins - physiology; Inflammation - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia - metabolism; Neurodegenerative Diseases - metabolism; Parkinson Disease - metabolism; Receptor, Adenosine A2A - metabolism; Signal Transduction - drug effects
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awy351

Increased adenosine signalling is deleterious in Parkinson's disease, whereas adenosine A2A receptor blockade is beneficial. Meng et al. report that CD73-derived adenosine enhances A2A receptor activity by inhibiting dopamine signalling. Targeting CD73 to reduce adenosine production alleviates inflammation and improves neuronal survival in disease models, representing a promising therapeutic strategy. Abstract Ectonucleotidase-mediated ATP catabolism provides a powerful mechanism to control the levels of extracellular adenosine. While increased adenosine A2A receptor (A2AR) signaling has been well-documented in both Parkinson's disease models and patients, the source of this enhanced adenosine signalling remains unclear. Here, we show that the ecto-5′-nucleotidase (CD73)-mediated adenosine formation provides an important input to activate A2AR, and upregulated CD73 and A2AR in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease models coordinatively contribute to the elevated adenosine signalling. Importantly, we demonstrate that CD73-derived adenosine-A2AR signalling modulates microglial immunoresponses and morphological dynamics. CD73 inactivation significantly attenuated lipopolysaccharide-induced pro-inflammatory responses in microglia, but enhanced microglia process extension, movement and morphological transformation in the laser injury and acute MPTP-induced Parkinson's disease models. Limiting CD73-derived adenosine substantially suppressed microglia-mediated neuroinflammation and improved the viability of dopaminergic neurons and motor behaviours in Parkinson's disease models. Moreover, CD73 inactivation suppressed A2AR induction and A2AR-mediated pro-inflammatory responses, whereas replenishment of adenosine analogues restored these effects, suggesting that CD73 produces a self-regulating feed-forward adenosine formation to activate A2AR and promote neuroinflammation. We further provide the first evidence that A2A enhanced inflammation by antagonizing dopamine-mediated anti-inflammation, suggesting that the homeostatic balance between adenosine and dopamine signalling is key to microglia immunoresponses. Our study thus reveals a novel role for CD73-mediated nucleotide metabolism in regulating neuroinflammation and provides the proof-of-principle that targeting nucleotide metabolic pathways to limit adenosine production and neuroinflammation in Parkinson's disease might be a promising therapeutic strategy.