Biological interplay between proteoglycans and their innate immune receptors in inflammation

Authors

  • Helena Frey,

    1. Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität Frankfurt am Main, Germany
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  • Nina Schroeder,

    1. Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität Frankfurt am Main, Germany
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  • Tina Manon-Jensen,

    1. Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität Frankfurt am Main, Germany
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  • Renato V. Iozzo,

    1. Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
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  • Liliana Schaefer

    Corresponding author
    • Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität Frankfurt am Main, Germany
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Correspondence

L. Schaefer, Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt am Main, Haus 74, Z. 3.108a, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany

Fax: +49 69 6301 83027

Tel: +49 69 6301 7899

E-mail: schaefer@med.uni-frankfurt.de

Abstract

An emerging body of evidence indicates that secreted proteoglycans act as signaling molecules, in addition to their canonical function in maintaining and regulating the architecture of various extracellular matrices. Proteoglycans interact with a number of receptors that regulate growth, motility and immune response. In part, as a consequence of their complex structure, proteoglycans can induce crosstalk among various families of receptors and can also interact with natural receptor ligands, often blocking and sequestering their bioactivity. In their soluble form, originating from either partial proteolytic processing or through de novo synthesis by activated cells, some proteoglycans can become potent danger signals, denoting tissue stress and injury. Recently, it has been shown that proteoglycans, especially those belonging to the small leucine-rich and hyaluronan-binding gene families as well as the glycosaminoglycan hyaluronan, act as endogenous ligands of the toll-like receptors, a group of central receptors regulating innate immunity. Furthermore, proteoglycans can activate intracellular inflammasomes and trigger sterile inflammation. In this review, we critically assess the signaling events induced by the proteoglycans biglycan, decorin, lumican and versican as well as hyaluronan during inflammation. We discuss the intriguing emerging notion that, in spite of structural diversity of biglycan, decorin, versican and hyaluronan, all of them signal through the same toll-like receptors, albeit triggering differential responses and biological outcomes. Finally, we review the modes of action of these endogenous ligands of toll-like receptors and their ability to specifically modify the final signaling events and the inflammatory response.

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