Feed-forward inhibition of CD73 and upregulation of adenosine deaminase contribute to the loss of adenosine neuromodulation in postinflammatory ileitis.

Abstract

Purinergic signalling is remarkably plastic during gastrointestinal inflammation. Thus, selective drugs targeting the "purinome" may be helpful for inflammatory gastrointestinal diseases. The myenteric neuromuscular transmission of healthy individuals is fine-tuned and controlled by adenosine acting on A(2A) excitatory receptors. Here, we investigated the neuromodulatory role of adenosine in TNBS-inflamed longitudinal muscle-myenteric plexus of the rat ileum. Seven-day postinflammation ileitis lacks adenosine neuromodulation, which may contribute to acceleration of gastrointestinal transit. The loss of adenosine neuromodulation results from deficient accumulation of the nucleoside at the myenteric synapse despite the fact that the increases in ATP release were observed. Disparity between ATP outflow and adenosine deficit in postinflammatory ileitis is ascribed to feed-forward inhibition of ecto-5'-nucleotidase/CD73 by high extracellular ATP and/or ADP. Redistribution of NTPDase2, but not of NTPDase3, from ganglion cell bodies to myenteric nerve terminals leads to preferential ADP accumulation from released ATP, thus contributing to the prolonged inhibition of muscle-bound ecto-5'-nucleotidase/CD73 and to the delay of adenosine formation at the inflamed neuromuscular synapse. On the other hand, depression of endogenous adenosine accumulation may also occur due to enhancement of adenosine deaminase activity. Both membrane-bound and soluble forms of ecto-5'-nucleotidase/CD73 and adenosine deaminase were detected in the inflamed myenteric plexus. These findings provide novel therapeutic targets for inflammatory gut motility disorders.

• Authors: Cátia Vieira, Maria Teresa Magalhães-Cardoso, Fátima Ferreirinha, Isabel Silva, Ana Sofia Dias, Julie Pelletier, Jean Sévigny, Paulo Correia-de-Sá
• Journal: Mediators of inflammation (Mediators Inflamm) Vol. 2014 Pg. 254640 ( 2014) ISSN: 1466-1861 [Electronic] United States
• PMID: 25210228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Trinitrobenzenesulfonic Acid
• 5'-Nucleotidase
• Adenosine Deaminase
• Adenosine

Topics

• 5'-Nucleotidase (metabolism)
• Adenosine (metabolism)
• Adenosine Deaminase (metabolism)
• Animals
• Female
• Ileitis (chemically induced, metabolism)
• Male
• Rats
• Trinitrobenzenesulfonic Acid (toxicity)