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 trough 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.

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

“…Lumican is present in human and murine lungs, and serum lumican levels are increased following lung inflammation and asthma (50,60,61). To determine whether lung lumican levels are up-regulated in pulmonary fibrosis, we stained lung tissue from mice that aspirated bleomycin or saline.…”

Versican: a novel modulator of hepatic fibrosis

“…Given the importance of versican turnover in modulation of cellular functions and fibrosis in other tissues, 51,69 we next investigated whether versican was being proteolytically processed, using a neo-epitope antibody to the well-documented DPEAAE↓ARRGQ cleavage site (anti-DPEAAE), present in Figure 3 Versican expression increases during liver fibrosis and reduces during recovery. (a) Total RNA was extracted from the livers of control mice, CCl 4 4-week treated mice and mice recovering from CCl 4 -induced liver injury and analyzed by qPCR for versican and collagen-1 mRNA expression using 18 s RNA as endogenous control.…”

“…[63][64][65][66][67][68] It is becoming increasingly clear that the regulated expression and proteolytic processing of versican are critically involved in influencing cell phenotype during inflammation and remodeling. 51,69 Bioactive ECM proteolytic fragments are increasingly recognized to regulate cellular function and have been generally referred to as matrikines. 70 Recently, the G1-DPEAAE 441 neo-epitope cleavage product of versican V1 has been dubbed 'versikine' to underscore the importance of versican cleavage in general and this versican cleavage product, in particular, in regulating tissue remodeling.…”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…In contrast, fragmented LMW HA stimulates expression of pro-inflammatory cytokines, chemokines, and growth factors (9,10). It can also activate intracellular inflammasomes (11), trigger sterile inflammation (12,13), and participate in cancer progression (14,15). There has been significant progress in understanding the immunoregulatory and signaling role of HA in many clinical and experimental conditions; however, the mechanisms of HA actions in lipid mediator signaling have not been extensively studied.…”