Biological interplay between proteoglycans and their innate immune receptors in inflammation

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.

Figure 1. Interaction of biglycan, decorin, and versican with TLRs and downstream signaling events

Soluble biglycan and decorin, two endogenous ligands of TLR2 and TLR4, stimulate the expression of chemokines and cytokines, including pro-IL-1β and IL-10, via NF-κB. By clustering TLR2, TLR4, and the P2X₇/P2X₄ receptors, biglycan activates the NLRP3/ASC- inflammasome, promoting maturation of pro-IL-1β to active IL-1β. Decorin blocks the binding of TGF-β1 to its receptor, thereby suppressing the maturation of miR-21, a posttranscriptional inhibitor of PDCD4. Consequently, enhanced PDCD4 levels inhibit the translation of the anti-inflammatory cytokine IL-10. Versican activates TLR2 and TLR6 in a CD14-dependent manner, inducing the expression of TNFα, IL-6 and several growth factors. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; IL, interleukin; miR-21, microRNA-21; NF-κB, nuclear factor κB; NLRP3, NOD-like receptor protein 3; PDCD4, programmed cell death protein 4; TGF-β1, transforming growth factor-β1; TLR, Toll-like receptor; TNFα, tumor necrosis factor α.

Figure 2. Hyaluronan-mediated signaling depends on its molecular weight

Low-molecular weight (LMW) hyaluronan exerts pro-inflammatory effects by: i) interacting with TLR2 and TLR4 and by NF-κB-dependent synthesis of pro-inflammatory cytokines (e.g. pro-IL-1β) and chemokines and ii) CD44-dependent internalization and fragmentation into HA-oligosaccharides. HA-oligosaccharides activate the NLRP3/ASC inflammasome and caspase-1 followed by processing of pro-IL-1β into mature IL-1β. High-molecular weight (HMW) hyaluronan exerts anti-inflammatory effects by: i) preventing LMW HA/TLR2 signaling; ii) CD44-dependent down-regulation of the expression of IL-8, TNFα, and iNOS and iii) forming cable-like structures, which sequestrate leukocytes and prevent their activation. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; HA, hyaluronan; HMW, high molecular weight; IL, interleukin; LMW, low molecular weight; NF-κB, nuclear factor-κB; NLRP3, NOD-like receptor protein 3; iNOS, inducible nitric oxide synthase; TLR, Toll-like receptor; TNFα, tumor necrosis factor α.