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CXCR3 ligands in disease and therapy

https://doi.org/10.1016/j.cytogfr.2014.11.009Get rights and content

Highlights

  • We introduce the various chemokines acting on the receptor CXCR3, including not only the IFN-γ-inducible CXCR3 ligands but also the platelet-derived ligands, namely CXCL4 and CXCL4L1.

  • We give an overview of the broad range of disorders (malignant, angiogenic, infectious, inflammatory and other) that have been associated with the CXCR3 ligands.

  • We elaborate on the promising therapeutic applicability of CXCR3 ligand administration or blockade and the potential use of the CXCR3 ligands as predictive or prognostic biomarkers.

Abstract

Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines.

Section snippets

An introduction to chemokines

Originally discovered to be chemotactic cytokines leading the way for leukocytes in health and inflammation, the chemokines have now made a name for themselves as pleiotropic molecules involved in a range of physiological as well as pathological processes [1], [2]. Most of their effects are established by signaling through a set of chemokine receptors, typically G protein-coupled receptors (GPCR). Notably, chemokine ligand/receptor binding is both a promiscuous and a redundant interaction,

The CXCR3 receptor

The CXCR3 receptor is a seven-transmembrane GPCR, classified as a CXC-type receptor based on the structure of its chemokine ligands. This receptor was indeed originally cloned and characterized as an activated T lymphocyte-expressed GPCR selective for ELR-negative CXC chemokines CXCL9 and CXCL10 [13]. In contrast to other chemokine receptors, the human CXCR3 gene was allocated to the X chromosome, in the q13 region [23]. In culture, the percentage of CXCR3-positive T lymphocytes has been shown

CXCR3 ligands in disease

Given their pleiotropic nature, CXCR3 ligands play their part in a myriad of diseases. Involvement of all CXCR3 ligands has been observed in various angiogenesis-related pathologies as well as immunological disorders, the latter being mostly related to autoimmunity or infection [45], [46]. Here we discuss a varied and extensive, yet not exhaustive, repertoire of diseases having been associated with CXCL4, CXCL4L1, CXCL9, CXCL10 or CXCL11. The CXCR3 ligands are indeed characterized by their

CXCR3 ligands in therapy

A great range of pathologies, mostly characterized by inflammation or vascular effects, have clearly been associated with changes in the expression levels of CXCR3 and CXCR3-binding chemokines (summarized in Table 2). More importantly, often the expression of these chemokine ligands and receptor correlates with pathogenesis, disease progression and prognosis or, under particular conditions, could reflect a failing compensation mechanism. Insight into CXCR3 biology has consequently inspired the

Summary

CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11 all bind, with varying affinity, to different splice variants of the CXCR3 receptor and are therefore collectively referred to as the CXCR3 ligands. Their pleiotropic character, regulating both leukocyte migration and angiogenesis, implicates these chemokines in a broad spectrum of diseases and their pathogenesis. Consequently, the CXCR3 ligands have attracted attention as new therapeutic targets. However, the field is still lacking fundamental

Acknowledgements

The authors would like to thank for granted support by the Fund for Scientific Research of Flanders (FWO-Vlaanderen project G.0764.14 and G.0773.13), the Interuniversity Attraction Poles Programme initiated by the Belgian Science Policy Office (I.A.P. project P7/40) and the Concerted Research Actions of the Regional Government of Flanders (GOA13/014).

Katrien Van Raemdonck graduated as master in biomedical sciences in 2009 and obtained a PhD in biomedical sciences in 2014, under the promotership of Prof. Dr. Sofie Struyf and Prof. Dr. Jo Van Damme at the Rega Institute, University of Leuven, Belgium. Her research interests are primarily focused on the role of chemokines in angiogenesis and cancer.

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    Katrien Van Raemdonck graduated as master in biomedical sciences in 2009 and obtained a PhD in biomedical sciences in 2014, under the promotership of Prof. Dr. Sofie Struyf and Prof. Dr. Jo Van Damme at the Rega Institute, University of Leuven, Belgium. Her research interests are primarily focused on the role of chemokines in angiogenesis and cancer.

    Philippe E. Van den Steen graduated as bio-engineer in 1997 at the University of Leuven in Belgium. He obtained his PhD degree in medical sciences in 2001 at the Laboratory of Immunobiology (Rega Institute, KU Leuven), with the glycosylation and substrates of gelatinase B/matrix metalloproteinase-9 as research topic. Subsequently, he started a novel malaria research line at the Rega Institute and performed a research stay at the London School of Hygiene and Tropical Medicine. Presently, he is holding a research professorship at the Rega Institute and his research is focusing on the immunobiology of malaria complications.

    Sandra Liekens graduated as bio-engineer in 1994 at the University of Leuven, Belgium. She obtained her PhD degree (2000) in applied biological sciences at the Rega Institute (Laboratory of Virology and Chemotherapy, University of Leuven, Belgium) on the inhibition of vascular tumor growth by anti-angiogenic and apoptosis-inducing agents. She is holding a position of professor at the Rega Institute. Her research is currently focused on understanding the interplay between viral and cellular factors involved in angiogenesis and the characterization of anti-angiogenic and vascular-targeting agents.

    Jo Van Damme (1950, bio-engineer, PhD, University of Ghent, Belgium) is professor at the Medical Faculty of the University of Leuven, Belgium, and Head of the Laboratory of Molecular Immunology, at the Rega Institute for Medical Research. He was president of the European Cytokine Society (2001–2007). He has done pioneer work in cytokine research and was involved in the identification of several human interleukins and chemokines. His current research is dealing with the role of chemoattractants and post-translationally modified forms thereof in infection, inflammation and cancer.

    Sofie Struyf graduated as bio-engineer in 1996 at the University of Leuven, Belgium. She obtained her PhD degree (2002) in applied biological sciences at the Rega Institute (Laboratory of Molecular Immunology, University of Leuven, Belgium) on post-translational modifications of chemokines. She is holding a position of professor at the Rega Institute. Her research is currently focused on the role of chemokines in angiogenesis and cancer.

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