Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

Significance Cyclic dinucleotides (CDNs) are important signaling molecules that are involved in many microbial processes and in the host cell response to intracellular pathogens. Intracellular CDN signaling is mediated by well-described sensor proteins; however, much less is known about how CDNs signal in the extracellular environment. Here we discover, in intestinal epithelial cells, that extracellular CDNs are hydrolyzed by enzymes present in the cell membrane to form adenosine and activate cell-surface adenosine receptors. This stimulates epithelial chloride secretion and inhibits cellular antiviral responses. Signaling originates exclusively from the serosal tissue-facing side of the epithelium. Our study implicates adenosine signaling as an important mechanism by which extracellular CDNs can modulate host defense at mucosal surfaces.