Human monocyte recognition of adenosine-based cyclic dinucleotides unveils the A2a Gαs protein-coupled receptor tonic inhibition of mitochondrially induced cell death.
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 of that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits protein kinase A (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 antiapoptotic. 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 dinucleotides unravels a novel proapoptotic pathway: the A2a Gαs protein-coupled receptor (GPCR)-driven tonic inhibitory signaling of mitochondrion-induced cell death.
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France ERL 5294 CNRS, Hôpital Purpan, Toulouse, France Laboratoire d'Excellence TOUCAN, Toulouse, France Institut Carnot CALYM, Pierre-Benite, France.
Marie
http://orcid.org/0000-0001-5278-5952
M
Tosolini
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France.
Frédéric
F
Pont
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France ERL 5294 CNRS, Hôpital Purpan, Toulouse, France Laboratoire d'Excellence TOUCAN, Toulouse, France Institut Carnot CALYM, Pierre-Benite, France.
Delphine
D
Bétous
Cayla-InVivoGen, Montaudran, France.
Emmanuel
E
Ravet
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France.
Laetitia
L
Ligat
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France.
Frédéric
F
Lopez
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France ERL 5294 CNRS, Hôpital Purpan, Toulouse, France Laboratoire d'Excellence TOUCAN, Toulouse, France Institut Carnot CALYM, Pierre-Benite, France.
Mary
M
Poupot
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France.
Marc
M
Poirot
Cayla-InVivoGen, Montaudran, France.
Éric
É
Pérouzel
Cayla-InVivoGen, Montaudran, France.
Gérard
G
Tiraby
CIRI, EVIR team, INSERM U1111, CNRS UMR5308, Université de Lyon-1, ENS de Lyon, Lyon, France INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France.
Els
E
Verhoeyen
INSERM UMR1037, Centre Recherches en Cancérologie de Toulouse, Toulouse, France Université Toulouse III Paul-Sabatier, Toulouse, France ERL 5294 CNRS, Hôpital Purpan, Toulouse, France Laboratoire d'Excellence TOUCAN, Toulouse, France Institut Carnot CALYM, Pierre-Benite, France jean-jacques.fournie@inserm.fr.
Jean-Jacques
JJ
Fournié
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D034741:RNA, Small Interfering; D043705:Receptor, Adenosine A2A; D000242:Cyclic AMP; D000241:Adenosine