Trends in Immunology
Volume 37, Issue 6, June 2016, Pages 399-411
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Review
Purinergic Signaling During Immune Cell Trafficking

https://doi.org/10.1016/j.it.2016.04.004Get rights and content

Trends

Nucleotides and nucleosides are well known for their intracellular functions as cellular energy currency ad as building blocks for DNA and RNA. In the extracellular compartment, however, they function as signaling molecules.

Nucleotides are converted in the extracellular compartment to nucleosides via the activity of enzymatic systems such as CD39 (conversion of ATP/ADP to AMP) and CD73 (conversion of AMP to adenosine).

Extracellular nucleotide signaling via P2 receptors drives inflammatory responses and is critical for bacterial killing. By contrast, nucleoside signaling via P1 receptors dampens inflammatory responses.

Enzymatic conversion of nucleotides into nucleosides can play a critical role in modulating an immune response associated with a shift from proinflammatory P2 signaling to anti-inflammatory P1 signaling.

Purinergic signaling modulates chemokine release and the outcome of the immune response. Pro- and anti-inflammatory effects mediated by extracellular nucleotides influence tissue fate either directly or through chemokine/chemokine receptor signaling.

Migration and positioning of immune cells is fundamental for their differentiation and recruitment at sites of infection. Besides the fundamental role played by chemokines and their receptors, recent studies demonstrate that a complex network of purinergic signaling events plays a key role in these trafficking events. This process includes the release of nucleotides (such as ATP and ADP) and subsequent autocrine and paracrine signaling events through nucleotide receptors. At the same time, surface-expressed ectoapyrases and nucleotidases convert extracellular nucleotides to adenosine, and adenosine signaling events play additional functional roles in leucocyte trafficking. In this review we revisit classical paradigms of inflammatory cell trafficking in the context of recent studies implicating purinergic signaling events in this process.

Section snippets

The Purinergic Network: Transducing Extracellular Nucleotide and Nucleoside Signaling

Nucleotides such as ATP, UTP, GTP, and ADP and the nucleoside adenosine are well known for their fundamental intracellular roles. ATP, for example, represents an ‘energy store’ for virtually all cells and in addition is a basic constituent of nucleic acids and a crucial enzyme modulator. Interestingly, nucleotides and nucleosides show completely different roles when present in the extracellular compartment. Hence, liberation of ATP, UTP, UDP, ADP, and adenosine occurs in many cell types and in

Chemotactic Properties of Nucleotides and Nucleosides

To respond to an infection, immune cells have to reach tissue sites where invading microorganisms are present. Therefore, leukocytes are programmed to exit the circulation and move toward epicenters of infection/inflammation, guided by chemical gradients of various stimuli. The oriented migration of cells inside chemical gradients is termed ‘chemotaxis’ and is evoked by so-called ‘chemoattractants’, a large and heterogeneous group of chemicals including both soluble molecules produced by the

What Is the Link between Chemokines and Purinergic Signaling?

Recent studies have highlighted the link between purinergic signaling and chemotactic pathways activated during the immune response, and compelling evidence shows that nucleotides and nucleosides are endowed with the ability to modulate chemokine secretion 50, 51, 52, 53. Cell chemotaxis is preceded by membrane polarization and important morphological changes paralleled by redistribution of intracellular signal transduction proteins implicated in motility, directional sensing, and polarity.

P1 Receptors and Chemokines

Adenosine and its receptors play a fundamental role in the immune response mainly by down-modulating multiple cytokine expression and secretion [17]. Recent data have confirmed the role of adenosine in modulating chemokine secretion and chemokine receptor activation and a deep investigation has been undertaken to shed light on the complex interplay between adenosine and chemokines in tuning leukocyte functions 63, 64, 65, 66, 67 (Figure 2A). Most of these studies indicate that adenosine through

P2X Receptors and Chemokines

Activation of the P2X1 receptor by ATP promotes neutrophil chemotaxis, a process involving Rho kinase-dependent actomyosin-mediated contraction at the cell rear [62]. Due to the massive recruitment of leukocytes, excessive chemokine secretion can be deleterious for tissue integrity 16, 82. P2 purinergic signaling is actively involved in the potentiation of chemokine secretion induced by leukocyte peptides such as the human neutrophil antimicrobial peptides, thus increasing expression of CXCL8

P2Y Receptors and Chemokines

The involvement of Gi protein-coupled receptors, including P2Y receptors, in modulating chemokine secretion by immune cells emerged some years ago. This finding was supported by the observation that UDP stimulated the release of CXCL8 from LPS-matured human monocyte-derived dendritic cells, which are professional antigen-presenting cells obtained by in vitro differentiation of peripheral human monocytes in the presence of GM-CSF and IL-4 followed by maturation in the presence of bacterial

Ectonucleotidases and Chemokines

Nucleotide-metabolizing enzymes play a role in controlling the concentration of nucleotides available for P1 and P2 receptor activation 12, 13. In particular, their activity decreases ATP and ADP concentrations, thus dampening P2 receptor-mediated responses, while increasing adenosine concentration and, consequently, ‘protective’ P1-induced effects. Recent data indicate a role for these enzymes in modulating the secretion of various chemokines, and pharmacological inhibition or lack of

Concluding Remarks and Future Perspectives

Exaggerated inflammatory response is the basis of the pathogenesis of various diseases such as psoriasis, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, asthma, and multiple sclerosis 96, 97. Therefore, it is urgent to identify mechanisms and pathways underlying pathologic inflammatory states to reveal new therapeutic targets and novel treatments (see Outstanding Questions). Although chemokines are needed to mount an adequate defensive response, excessive chemokine secretion

Acknowledgments

The authors apologize to the many authors whose excellent work they could not cite owing to space limitation. The work was supported by National Institutes of Health grants R01 DK097075, R01-HL092188, R01- HL098294, POI-HL114457, and R01-HL119837 to H.K.E.

Glossary

Chemokinesis
random cell movement in the absence of a chemoattractant gradient.
Chemotaxis
oriented movement of cells or organisms in response to chemicals that attract (positive chemotaxis) or repel (negative chemotaxis) them.
CXCL8 (IL-8)
chemokine secreted by various cells (macrophages, endotheliocytes, epithelial and smooth muscle cells); binds to the CXCR1 and CXCR2 receptors.
CXCL12 (stromal-derived factor-1)
binds to CXCR4 and CXCR7 receptors regulating cell trafficking under normal and

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