Biological interplay between proteoglycans and their innate immune receptors in inflammation.
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.
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität Frankfurt am Main, Germany.
Helena
H
Frey
Nina
N
Schroeder
Tina
T
Manon-Jensen
Renato V
RV
Iozzo
Liliana
L
Schaefer
D000818:Animals; D058578:Biglycan / Q000276:immunology / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000276:immunology / Q000378:metabolism; D058575:Decorin / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000276:immunology; D007632:Keratan Sulfate / Q000276:immunology / Q000378:metabolism; D000071234:Lumican; D051379:Mice; D011509:Proteoglycans / Q000276:immunology* / Q000378:metabolism; D020239:Receptor Cross-Talk; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
C546885:Bgn protein, mouse; D058578:Biglycan; D011508:Chondroitin Sulfate Proteoglycans; C546879:Dcn protein, mouse; D058575:Decorin; D053583:Interleukin-1beta; C000604307:Lum protein, mouse; D000071234:Lumican; D011509:Proteoglycans; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D007632:Keratan Sulfate