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

Meng, F; Guo, ZG; Hu, YL; Mai, WH; Zhang, ZJ; Zhang, B; Ge, QQ; Lou, HF; Guo, F; Chen, JF; Duan, SM; Gao, ZH

Duan, SM; Gao, ZH (reprint author), Zhejiang Univ, Sch Med, Dept Neurobiol, Hangzhou, Peoples R China.; Duan, SM; Gao, ZH (reprint author), Zhejiang Univ, Sch Med, Affiliated Hosp 2, NHC & CAMS Key Lab Med Neurobiol, Hangzhou, Peoples R China.

BRAIN, 2019; 142 (): 700

Abstract

Ectonucleotidase-mediated ATP catabolism provides a powerful mechanism to control the levels of extracellular adenosine. While increased adenosine A(2A) receptor (A(2A)R) 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 A(2A)R, and upregulated CD73 and A(2A)R 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-A(2A)R 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 A(2A)R induction and A(2A)R-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 A(2A)R and promote neuroinflammation. We further provide the first evidence that A(2A) 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.

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