Pro-inflammatory roles of chondroitin sulfate proteoglycans in disorders of the central nervous system

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…Growth factors that increase during inflammation such as platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGFβ) increase CS chains length and alter CS composition, impacting the ability of versican to interact with other molecules (35,(48)(49)(50). The CS isolated from versican interacts with inflammatory cytokines and impacts cytokine activity (51) [also see reviews (52,53)]. Interestingly, the machinery and signaling pathways that control the composition and elongation of the CS chain differ from those controlling the transcription of versican core protein synthesis (48).…”

“…Versican is essential during development (76,77) and it is now becoming apparent that it is an important component of the tissue inflammation caused by infection and tissue injury (10). Versican accumulates as part of the early inflammatory response in a number of human diseases often associated with the invasion of leukocytes including those in the vascular system (10,40,(78)(79)(80)(81)(82)(83)(84), lung (5,6,60,77,(85)(86)(87)(88)(89), brain and spinal cord (53,(90)(91)(92), intestine (93)(94)(95)(96), heart (97), liver (63), skin (98,99), eye (100, 101), pancreatic islets (102), and many different forms of cancer [reviewed in (103)(104)(105)]. The accumulation of versican in these tissues is usually associated with other ECM components that bind versican, such as hyaluronan (106,107), link protein, TSG-6, IαI, and CD44 (95, 96, 108-111) (Figure 1).…”

“…The negatively charged CS chains in large part control the ability of versican to interact with a multitude of other molecules including chemokines, growth factors and proteases (51,52,122,(126)(127)(128) impacting their bioavailability and bioactivity (129)(130)(131). A number of studies demonstrate that CS chains can also promote the release of proinflammatory cytokines from macrophages and splenocytes, regulate MHCII intracellular trafficking, antigen presentation and T-cell activation [reviewed in (53)].…”

The Influence of the Extracellular Matrix in Inflammation: Findings from the SPARC‐Null Mouse

“…Localized expressions of structural ECM and matricellular proteins have the potential to drive initiating deposition of disorganized ECM that leads to fibrotic ECM accumulation. Mounting evidence that the structure and composition of the ECM are critical factors influencing inflammatory cell activation in tissues implies that expression of matricellular proteins by infiltrating and/or resident cells will modulate inflammatory progression and ECM remodeling (Gordts and Esko, ; Stephenson and Yong, ; Yamauchi et al, ). SPARC (BM40/osteonectin) is a secreted, collagen‐binding protein shown to be an important modulator of procollagen processing and collagen fibril assembly in connective tissues.…”

“…Hence, reductions in the size and number of collagen fibrils and fibers will influence amounts of SLRPs accommodated in the ECM. As SLRPs are known to play important roles in inflammatory processes, the changes in the profile of SLRPs in SPARC‐null connective tissue are likely to also influence inflammatory cell behavior (Stephenson and Yong, ). For example, Arnold et al () reported a reduction in levels of decorin expression in the ECM surrounding pancreatic tumors grown in SPARC‐null mice.…”