Trends in Immunology
ReviewPurinergic Signaling During Immune Cell Trafficking
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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