title: Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity.
abstract: Evolving studies in models of transplant rejection, inflammatory bowel disease, and cancer, among others, have implicated purinergic signaling in clinical manifestations of vascular injury and thrombophilia, inflammation, and immune disturbance. Within the vasculature, spatial and temporal expression of CD39 nucleoside triphosphate diphosphohydrolase (NTPDase) family members together with CD73 ecto-5'-nucleotidase control platelet activation, thrombus size, and stability. This is achieved by closely regulated phosphohydrolytic activities to scavenge extracellular nucleotides, maintain P2-receptor integrity, and coordinate adenosinergic signaling responses. The CD38/CD157 family of extracellular NADases degrades NAD(+) and generates Ca(2+)-active metabolites, including cyclic ADP ribose and ADP ribose. These mediators regulate leukocyte adhesion and chemotaxis. These mechanisms are crucial in vascular homeostasis, hemostasis, thrombogenesis, and during inflammation. There has been recent interest in ectonucleotidase expression by immune cells. CD39 expression identifies Langerhans-type dendritic cells and efficiently distinguishes T regulatory cells from other resting or activated T cells. CD39, together with CD73 in mice, serves as an integral component of the suppressive machinery of T cells. Purinergic responses also impact generation of T helper-type 17 cells. Further, CD38 and changes in NAD(+) availability modulate ADP ribosylation of the cytolytic P2X7 receptor that deletes T regulatory cells. Expression of CD39, CD73, and CD38 ectonucleotidases on either endothelial or immune cells allows for homeostatic integration and control of vascular inflammatory and immune cell reactions at sites of injury. Ongoing development of therapeutic strategies targeting these and other ectonucleotidases offers promise for the management of vascular thrombosis, disordered inflammation, and aberrant immune reactivity.
authors.affiliation: Department of Genetics, Biology, and Biochemistry, University of Turin & Human Genetics Foundation, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Deaglio
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007109:Immunity; D007249:Inflammation / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000378:metabolism*
chemical_list: D011983:Receptors, Purinergic; D015720:5'-Nucleotidase