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Cell-surface enzymes in control of leukocyte trafficking

Nature Reviews Immunology volume 5, pages 760–771 (2005)Cite this article

Key Points

  • Ectoenzymes are membrane proteins that have their catalytically active sites in the extracellular environment. Leukocytes and endothelial cells express many ectoenzymes, and they have recently been shown to be involved in leukocyte trafficking from the blood into the tissues, under physiological and inflammatory conditions.

  • Extracellular nucleotide metabolism, which involves ectonucleotidases (CD39 and CD73) and adenosine deaminase, regulates ATP and adenosine concentrations. Adenosine inhibits the function of many leukocyte and endothelial cell-adhesion molecules and decreases vascular permeability, which results in attenuated inflammatory reactions.

  • Chemotaxis is regulated by ecto-ADP-ribosyl cyclases (CD38 and CD157) and ectopeptidases (CD10, CD13 and CD26). CD38-mediated signalling promotes chemotaxis towards certain chemokines, whereas proteolytic trimming of chemokines by peptidases, in most cases, decreases their potency to attract leukocytes.

  • Vascular adhesion protein 1 (VAP1) is an endothelial-cell-expressed ecto-oxidase that regulates leukocyte rolling, firm adhesion and transmigration.

  • The availability of substrates, inhibitors and cofactors for ectoenzymes can dynamically regulate leukocyte extravasation. Moreover, many of the end-products of the enzymatic reactions are biologically active substances that trigger responses in their target cells.

  • The activity of ectoenzymes can be therapeutically modulated to treat inappropriate inflammation. Inhibiting migration-promoting ectoenzymes (such as CD38 and VAP1) with small-molecule enzyme inhibitors or increasing (for example, by providing more substrate) the activity of migration-suppressing ectoenzymes (such as CD26 and endothelial-cell-expressed CD73) will provide promising new forms of anti-adhesive therapy.

  • The role in leukocyte trafficking of most ectoenzymes that are expressed by leukocytes and endothelial cells has not been tested, although many of these enzymes regulate the migration of other cell types. Emerging biological tools (such as gene-targeted animals) should provide further insight into how these multifunctional molecules are involved in leukocyte extravasation.

Abstract

Leukocyte trafficking between the blood and the tissues is pivotal for normal immune responses. Cell-adhesion molecules (such as selectins and leukocyte integrins) and chemoattractants (such as chemokines) have well-established roles in supporting leukocyte exit from the blood. Emerging data now show that, for both leukocytes and endothelial cells, enzymatic reactions that are catalysed by cell-surface-expressed enzymes with catalytic domains outside the plasma membrane (known as ectoenzymes) also make crucial contributions to this process. Ectoenzymes can function physically as adhesion receptors and can regulate the recruitment of cells through their catalytic activities. Here, we provide new insights into how ectoenzymes — including nucleotidases, cyclases, ADP-ribosyltransferases, peptidases, proteases and oxidases — guide leukocyte traffic.

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Figure 1: Ectoenzymes and the leukocyte-extravasation cascade.
Figure 2: Extracellular ATP metabolism and leukocyte trafficking.
Figure 3: Extracellular NAD(P) metabolism and leukocyte trafficking.
Figure 4: A model of the action of vascular adhesion protein 1 during leukocyte–endothelial-cell interaction.

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Acknowledgements

We thank F. Marttila-Ischihara for the intravital-microscopy video and G. Yegutkin for critical reading of the manuscript.

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Authors and Affiliations

  1. MediCity Research Laboratory, University of Turku, Tykistökatu 6A, Turku, 20520, Finland

    Marko Salmi & Sirpa Jalkanen

  2. Department of Medical Microbiology, University of Turku, Kiinamyllynkatu 13, Turku, 20520, Finland

    Marko Salmi & Sirpa Jalkanen

  3. Department of Bacterial and Inflammatory Diseases, National Public Health Institute, Tykistökatu 6A, Turku, 20520, Finland

    Marko Salmi & Sirpa Jalkanen

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  1. Marko Salmi
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Correspondence to Marko Salmi.

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Competing interests

Sirpa Jalkanen owns shares in a Finnish biotechnology company that is targeting one of the molecules (VAP1) described in this Review.

Supplementary information

Supplementary Information S1

S1 | Leukocyte-extravasation cascade in vivo. Leukocyte-endothelial-cell contacts were visualized in a living, anaesthetized mouse, using intravital microscopy. In an inflamed venule of cremaster muscle, numerous rolling cells can be seen (moving from top to bottom). There are also many firmly adherent leukocytes (some indicated by red arrows) and cells that have transmigrated (some indicated by blue arrows). Non-interacting cells (for example, erythrocytes) move too fast to be distinguished as individual cells.The blood flow is from the top to the bottom. The video runs at real-time speed, and the yellow bar indicates a distance of 30µm. (AVI 1618 kb)

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DATABASES

Entrez Gene

adenosine deaminase

ART2

autotaxin

CD10

CD13

CD26

CD38

CD39

CD73

CD156b

CD157

VAP1

FURTHER INFORMATION

Department of Bacterial and Inflammatory Diseases

Sirpa Jalkanen's homepage

Glossary

EXTRAVASATION CASCADE

The multistep process during which a leukocyte migrates from the blood into the tissue through the blood-vessel wall.

CHEMOKINES

Most chemokines are short, soluble peptides that bind serpentine receptors to trigger leukocyte activation and directed movement. Most chemokines belong to the CC-chemokine ligand (CCL) and CXC-chemokine ligand (CXCL) families, which are defined on the basis of their protein sequence. Chemokine receptors are named CC-chemokine receptor (CCR) and CXC-chemokine receptor (CXCR) depending on whether they bind mainly CCL or CXCL chemokines, respectively.

EC NUMBER

(Enzyme commission number). A number that belongs to an international classification of enzymes.

ISCHAEMIA-REPERFUSION INJURY

An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.

fMLP

(N-formyl-methionyl-leucyl-phenylalanine). A bacterial peptide that is a highly potent chemoattractant, especially for granulocytes.

TOPA-QUINONE

A modified tyrosine residue (2,4,5-trihydroxyphenylalanyl quinone) that is required for the enzymatic activity of certain amine oxidases.

SCHIFF BASE

The functional group or compound that contains a carbon–nitrogen double bond.

HYDROGEN PEROXIDE

A potent signalling molecule and inflammatory mediator that is a reactive oxygen species.

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Salmi, M., Jalkanen, S. Cell-surface enzymes in control of leukocyte trafficking. Nat Rev Immunol 5, 760–771 (2005). https://doi.org/10.1038/nri1705

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