Trends in Molecular Medicine
ReviewFeature ReviewCD39 and CD73 in immunity and inflammation
Section snippets
How the purinergic system shapes immune/inflammatory responses
The immune system is a tightly regulated and integrated cell network that functions to preserve and restore homeostasis. This task is accomplished by patrolling organs for signs of microbial invasion or tissue injury and triggering defensive inflammatory and restitutive responses following infection and injury [1]. However, inappropriate activation of the immune system can lead to unacceptable levels of collateral tissue damage and the development of various pathophysiological conditions, such
Molecular biology and regulation of CD39 and CD73
CD39 is an integral membrane protein that phosphohydrolyzes ATP, and less efficiently ADP, in a Ca2+- and Mg2+-dependent manner, to yield AMP [18]. Human CD39 is a putative 510-amino acid protein with seven potential N-linked glycosylation sites, 11 Cys residues, and two transmembrane regions [19]. Structurally, it is characterized by two transmembrane domains, a small cytoplasmic domain comprising the NH2- and COOH-terminal segments, and a large extracellular hydrophobic domain, which includes
The function of CD39 and CD73 in cells of the immune system
Given that the combination of CD39 and CD73 degrade ATP, ADP, and AMP to adenosine, they can be viewed as ‘immunological switches’ that shift ATP-driven proinflammatory immune cell activity toward an anti-inflammatory state mediated by adenosine (Figure 1) [36]. In addition to host cells, several pathogens (i.e., Escherichia coli, Staphylococcus aureus, Toxoplasma gondii, and Trichomonas vaginalis) are endowed with a streamlined CD39/CD73-like machinery, which fosters the establishment and
Regulation of immunity by ectonucleotidases in infections
There is increasing evidence that the ability of several microorganisms to evade the control of the immune system arises from their high nucleotide metabolic versatility, which favors their invasion of and dissemination in the host [80]. Pathogens can also exploit ectonucleotidases located on the outer surface of a cell or tissue to generate an adenosine-rich milieu, which allows them to escape immune surveillance 81, 82, 83, 84, 85. By contrast, in certain scenarios, CD39 and CD73 can also
Regulation of immunity by CD39 and CD73 in autoimmune diseases
Alteration of the CD39/CD73 machinery can disrupt the complex mechanisms underlying immune tolerance to self-antigens, driven mainly by Tregs, thus contributing to the development of several autoimmune diseases [25].
Regulation of immunity by CD39 and CD73 in allergic diseases
The growing awareness about the involvement of purinergic signaling in shaping immune and inflammatory responses during allergic reactions [112] has fostered scientific interest in the roles of CD39 and CD73 in this context. Recently, a key role for CD73 has been unraveled in the development of airway inflammation after allergen exposure, as mice lacking CD73 display reduced airway hyperresponsiveness to methacholine as well as decreased eosinophil and mast cell infiltration, as compared with
Regulation of immunity by CD39 and CD73 in ischemia–reperfusion injury
Multiple lines of evidence have demonstrated that adenosine, produced as a result of the coordinated function of CD39 and CD73, is pivotal in protecting tissue against hypoxic and ischemic insults. Early studies, based on both genetic knockout models and pharmacological inhibition of CD39 and CD73 in mice, showed that these enzymes are crucial for protecting against increased vascular permeability and neutrophil extravasation during local hypoxia 32, 34, 59. The increased vascular permeability
Regulation of immunity by CD39 and CD73 in atherosclerosis and arterial calcification
Current knowledge about the complex mechanisms underlying the pathogenesis of atherosclerosis highlights the importance of several immune/inflammatory mediators in the initiation and progression of this disorder [129], and vascular CD39 and CD73 regulate several steps in the atherogenic process by governing purinergic signaling 130, 131.
Apolipoprotein E (ApoE) knockout mice, an experimental model of atherosclerosis, show decreased CD39 expression and activity in thoracic aorta, which correlates
Regulation of immunity by CD39 and CD73 in diabetes
The term diabetes denotes a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both [139]. Diabetes can result from the autoimmune destruction of β cells in the pancreas with consequent insulin deficiency (type 1 diabetes) or abnormalities of adipose tissue, liver, and muscle that result in resistance to insulin action (type 2 diabetes) [139].
A recent study has demonstrated that the susceptibility of mice to
Regulation of immunity by CD39 and CD73 in cancer
Increasing evidence suggests that interactions between tumor cells and their microenvironment are essential for tumorigenesis [145]. Within the neoplastic milieu, cancer and immune cells closely interact to generate an immunosuppressive environment by releasing immunomodulatory factors, which supports neoplastic growth [146].
Several studies have pointed to the critical task carried out by CD39 and CD73 in generating this immunosuppressed environment, characterized by increased adenosine levels,
Concluding remarks
Over the past 30 years, increasing evidence has underscored the role of the purinergic system in coordinating tissue immune responses under both physiological conditions and in the presence of inflammation. In this context, the CD39/CD73 pathway is a critical checkpoint; through its coordinated activity, it regulates the types and level of purinergic receptor activation, by finely shaping the chemistry, magnitude, and duration of purinergic signaling, in accordance with the various
Acknowledgments
This work was supported by National Institutes of Health grant R01GM66189 and USAMRMC grant 09065004.
Glossary
- Arteriogenesis
- describes the growth of functional collateral arteries from pre-existing arterio-arteriolar anastomoses in response to ischemia.
- Atheroma
- is an asymmetric focal thickening of the intima. The atheroma is composed of a lipid core, a residue of necrotic ‘foam cell-forming macrophages’, that migrate into the intima and ingest lipids, as well as by a connective tissue matrix derived from smooth muscle cells that migrate from the media into the intima, where they proliferate and change
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