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

Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27502-27508. doi: 10.1073/pnas.2015919117. Epub 2020 Oct 21.


Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNβ expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2B adenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.

Keywords: adenosine; cyclic dinucleotide; epithelial; intestine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / metabolism
  • Adenosine / metabolism*
  • Cell Line, Tumor
  • Chlorides / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • GPI-Linked Proteins / metabolism
  • Humans
  • Immunity, Innate*
  • Immunity, Mucosal*
  • Interferon-beta / metabolism
  • Intestinal Mucosa / cytology
  • Nucleotides, Cyclic / metabolism*
  • Phosphoric Diester Hydrolases / metabolism
  • Poly I-C / immunology
  • Pyrophosphatases / metabolism
  • Receptor, Adenosine A2B / metabolism
  • Signal Transduction / immunology


  • ADORA2B protein, human
  • CFTR protein, human
  • Chlorides
  • GPI-Linked Proteins
  • Nucleotides, Cyclic
  • Receptor, Adenosine A2B
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Interferon-beta
  • 5'-Nucleotidase
  • NT5E protein, human
  • Phosphoric Diester Hydrolases
  • ectonucleotide pyrophosphatase phosphodiesterase 1
  • Pyrophosphatases
  • Adenosine
  • Poly I-C