Versican and the control of inflammation

Abstract

Versican is an extracellular matrix (ECM) proteoglycan that interacts with cells by binding to non-integrin and integrin receptors and to other ECM components that associate with the cell surface. Recent studies have shown also that versican interacts with myeloid and lymphoid cells promoting their adhesion and production of inflammatory cytokines. Versican is produced by stromal cells, as well as leukocytes, and is markedly increased in inflammation. Inflammatory agonists, such as double-stranded RNA mimetics (e.g., poly I:C), stimulate stromal cells, such as smooth muscle cells and fibroblasts, to produce fibrillar ECMs enriched in versican and hyaluronan (HA) that interact with leukocytes promoting their adhesion. Interference with the incorporation of versican into this ECM blocks monocyte adhesion and dampens the inflammatory response. Tumor cells also express elevated levels of versican which interact with myeloid cells to promote an inflammatory response, through stimulating cytokine release, and metastasis. In addition, myeloid cells, such as macrophages in tumors, synthesize versican which affects tumor cell phenotypes, inflammation, and subsequent metastasis. Versican, by binding to hyaluronan, influences T lymphocyte phenotypes and in part controls the ability of these cells to synthesize and secrete cytokines that influence the immune response. Collectively, these studies indicate that versican as an ECM molecule plays a central role in inflammation and as a result it is emerging as a potential target promising wide therapeutic benefits.

Versican: a novel modulator of hepatic fibrosis

“…In this model, it appears that processing of V0 occurs during injury and gradually decreases over 28 days of recovery, to a level less than control. Given the described roles of versican in inflammation, [52][53][54] the prolonged proteolytic turnover of versican is consistent with a period of sustained inflammation during resolution of fibrosis. Additionally, given that engagement of TLR2 by versican appears to be directly involved in the activation and the induction of inflammatory cytokine secretion, 83 our observation that hepatic fibrosis leads to a significant increase in versican fragments may indicate that versican processing contributes to the inflammatory response.…”

“…48,51 It is a central component of inflammatory processes and is involved in multiple protein-binding interactions and modulation of leukocytes and lympohocytes. 52,53 Versican has also been shown to activate macrophages through toll-like receptor 2 (TLR2) and its co-receptors, TLR6 and CD14, leading to the production of the proinflammatory cytokine TNF-α, in addition to macrophage activation. 54 Proteolytic processing of versican occurs by several different members of the ADAMTS (A Disintegrin-like and Metalloproteinase with Thrombospondin-1 motifs) family of enzymes.…”

Immunoregulatory roles of versican proteolysis in the myeloma microenvironment

“…3,4 VCAN has crucial, nonredundant significance in embryonic development 5 and emerging roles in cancer inflammation and metastasis. [6][7][8][9] VCAN promotes tolerogenic polarization of antigen-presenting cells through Toll-like receptor 2 (TLR2). 10 VCAN is proteolytically cleaved by ADAMTS-type proteases in a highly regulated manner.…”

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

“…This ECM is strongly adhesive for monocytes and T lymphocytes and is hyaluronidase-sensitive, indicating that HA is a necessary component of this adhesive ECM (30 -33). Interfering with versican accumulation in this ECM also inhibits leukocyte adhesion in vitro, suggesting that versican and HA may form an immunomodulatory complex in response to viral lung infection (32)(33)(34). However, specific roles for versican in the regulation of pulmonary inflammatory responses are not yet well defined due to lack of versican knock-out animals, which are embryonically lethal due to defective cardiac development (35).…”