Human monocyte recognition of adenosine-based cyclic di-nucleotides unveils the A2a GPCR tonic inhibition of mitochondrial-induced cell death.

Tosolini M, Pont F, Bétous D, Ravet E, Ligat L, Lopez F, Poupot M, Poirot M, Pérouzel E, Tiraby G, Verhoeyen E, Fournié JJ. – 10/11/2014

Mol Cell Biol

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Cyclic dinucleotides are important messengers for bacteria and protozoa and are well-characterized immunity alarmins for infected mammalian cells through intracellular binding to STING receptors. We sought to investigate their unknown extracellular effects by adding cyclic dinucleotides to the culture medium of freshly-isolated human blood cells in vitro. Here we report that adenosine-containing cyclic dinucleotides induce the selective apoptosis of monocytes through a novel apoptotic pathway. We demonstrate that these compounds are inverse agonist ligands of A2a, a Gαs-coupled adenosine receptor selectively expressed by monocytes. Inhibition of monocyte A2a by these ligands induces apoptosis through a mechanism independent to that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits PKA activity, thereby recruiting cytosolic p53 which opens the mitochondrial permeability transition pore and impairs mitochondrial respiration, resulting in apoptosis. A2a antagonists and inverse agonist ligands induce apoptosis of human monocytes while A2a agonists are anti-apoptotic. In vivo, we used a mock developing human hematopoietic system through NSG mice transplanted with human CD34+ cells. Treatment with cyclic-di-AMP selectively depleted A2a-expressing monocytes and their precursors via apoptosis. Thus, monocyte recognition of cyclic di-nucleotides unravels a novel pro-apoptotic pathway: the A2a GPCR-driven tonic inhibitory signaling of mitochondrial-induced cell death.