Abstract
Ectonucleotidases are extracellular enzymes with a pivotal role in inflammation that hydrolyse extracellular purine and pyrimidine nucleotides, e.g., ATP, UTP, ADP, UDP, AMP and NAD+. Ectonucleotidases, expressed by virtually all cell types, immune cells included, either as plasma membrane-associated or secreted enzymes, are classified into four main families: 1) nucleoside triphosphate diphosphohydrolases (NTPDases), 2) nicotinamide adenine dinucleotide glycohydrolase (NAD glycohydrolase/ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1), 3) ecto-5′-nucleotidase (NT5E), and 4) ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs). Concentration of ATP, UTP and NAD+ can be increased in the extracellular space thanks to un-regulated, e.g., cell damage or cell death, or regulated processes. Regulated processes include secretory exocytosis, connexin or pannexin hemichannels, ATP binding cassette (ABC) transporters, calcium homeostasis modulator (CALMH) channels, the ATP-gated P2X7 receptor, maxi-anion channels (MACs) and volume regulated ion channels (VRACs). Hydrolysis of extracellular purine nucleotides generates adenosine, an important immunosuppressant. Extracellular nucleotides and nucleosides initiate or dampen inflammation via P2 and P1 receptors, respectively. All these agents, depending on their level of expression or activation and on the agonist concentration, are potent modulators of inflammation and key promoters of host defences, immune cells activation, pathogen clearance, tissue repair and regeneration. Thus, their knowledge is of great importance for a full understanding of the pathophysiology of acute and chronic inflammatory diseases. A selection of these pathologies will be briefly discussed here.
Highlights
It is thought that ATP might be the most ancient extracellular messenger used by primordial cells to send messages to their neighbours, or as a passive signal of danger or distress (Verkhratsky et al, 2020)
Extracellular ATP and UTP released from apoptotic cells mediate monocyte recruitment (Elliott et al, 2009), modulate phagocytosis (Soni et al, 2019; Zumerle et al, 2019), and support NLRP3 inflammasome-mediated IL-1β release (Ayna et al, 2012) (Figure 3B). Both NTPDase1/CD39 and NT5E/CD73 are expressed to high level in macrophages where they play a key role in the control of P2X7 receptor (P2X7R)-dependent responses and in the generation of adenosine (Levesque et al, 2010)
NTPDase1/CD39 and NT5E/CD73, both expressed on the surface of human FoxP3+ T regulatory (Treg) (9, 157), catalyse the generation of large amounts of adenosine that acts at A2A and A2B receptors to inhibit T cells responses (158)
Summary
It is thought that ATP might be the most ancient extracellular messenger used by primordial cells to send messages to their neighbours, or as a passive signal of danger or distress (Verkhratsky et al, 2020). Ectonucleotidases are enzymes designated to hydrolyse extracellular nucleotides, mainly ATP, UTP, and NAD+, which generate metabolites relevant to immune and inflammatory responses. Both NTPDase1/CD39 and NT5E/CD73 are expressed to high level in macrophages where they play a key role in the control of P2X7R-dependent responses and in the generation of adenosine (Levesque et al, 2010).
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