Adherent leukocytes prevent adenosine formation and impair endothelial barrier function by Ecto-5'-nucleotidase/CD73-dependent mechanism.
Extracellular purines are important signaling molecules that mediate both inflammatory (ATP, ADP) and anti-inflammatory (adenosine) effects in the vasculature. The duration and magnitude of purinergic signaling is governed by a network of purine-converting ectoenzymes, and endothelial and lymphoid cells are generally characterized by counteracting ATP-inactivating and ATP-regenerating/adenosine-eliminating, phenotypes, respectively. By using cultured human umbilical vein endothelial cells and normal or leukemic lymphocytes as an in vitro model of leukocyte-endothelial interactions, we have identified a link between the adhesion cascade and extracellular purine turnover. Upon adhesion, lymphocytes suppress endothelial purine metabolism via (i) inhibition of ecto-5'-nucleotidase/CD73-mediated AMP hydrolysis, (ii) rapid deamination of the remaining adenosine, and (iii) maintenance of the sustained pericellular ATP level through continuous nucleotide release and phosphotransfer reactions. Compensation of the loss of adenosine promotes vascular barrier function (measured as a paracellular flux of 70 kDa fluorescein isothiocyanate-dextran) and decreases transendothelial leukocyte migration. Together, these data show that adherent lymphocytes attempt to prevent adenosine formation in the endothelial environment that, as a consequence, may impair the vascular barrier function and facilitate the subsequent step of leukocyte transmigration into the tissue. These leukocyte adhesion-mediated shifts in the local nucleotide and nucleoside concentrations represent a previously unrecognized paracrine mechanism affecting the functional state of the targeted vascular endothelium and coordinately regulating lymphocyte trafficking between the blood and tissues.
Henttinen
Tiina
T
MediCity Laboratory and Department of Medical Microbiology, Turku University and National Public Health Institute, Finland.
Jalkanen
Sirpa
S
Yegutkin
Gennady G
GG
D015720:5'-Nucleotidase / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000502:physiology*; D019899:Paracrine Communication
D015720:5'-Nucleotidase