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

Brain. 2019 Mar 1;142(3):700-718. doi: 10.1093/brain/awy351.

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.

Keywords: CD73; Parkinson’s disease; adenosine A2AR; microglia; neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • GPI-Linked Proteins
  • Receptor, Adenosine A2A
  • 5'-Nucleotidase
  • NT5E protein, human
  • Adenosine
  • Dopamine