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Review
. 2011:61:301-32.
doi: 10.1016/B978-0-12-385526-8.00010-2.

Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity

Silvia Deaglio  1 , Simon C Robson
Affiliations
Review

Ectonucleotidases as regulators of purinergic signaling in thrombosis, inflammation, and immunity

Silvia Deaglio et al. Adv Pharmacol. 2011.

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.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
Purinergic mediators that are metabolized by CD39, CD73, and CD38 and respective receptors. Schematic depiction of extracellular nucleotides, for example, ATP, ADP, and NAD with derived adenosine nucleotide products as ligands for the corresponding purinergic receptors—see text for details of NAD catalysis by CD38 and impacts on purinergic signaling.
FIGURE 2
FIGURE 2. Schematic representation of regulation of T regulatory cell homeostasis by extracellular nucleotides
Extracellular nucleotide metabolism may be integrated into a homeostatic mechanism for the T cell compartment. Resting conditions are associated with limited ATP or NAD flux, low levels of CD39, CD38, and CD73. Basal mechanisms involve ADP ribosylation of P2X7, NICD, and maintenance of Treg compartment in quiescent state by low-level A2A stimulation (left panel). With acute inflammation and cellular stress, there are increases of pericellular nucleotides that induce cellular activation with resulting abrogation of select Treg responses (secondary to P2X7 activation). Those surviving cells exhibit marked upregulation of CD39, CD38, and CD73. Ultimately, NAD is converted and effectively removed by CD38, while ATP is subjected to hydrolysis by CD39 and CD73 (right panel). As these surviving immune suppressive cells are “protected” by ectonucleotidases and also have potent internal mechanisms to modulate cAMP, such cells, for example, Treg initially expand, and adenosine accumulates to then activate A2A receptors on T effector cells and NK cells (amongst others). This effect has the result of limiting effector cell expansion and blocking immune responses.
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