FIGURE 2.

Possible mechanisms for proteoglycans in metabolic inflammation. (A) GAG chains, in particular HS, bind and present soluble inflammatory mediators, such as cytokines and chemokines at the cell surface. They also protect those factors from proteolytic degradation. Moreover, they act as co-receptors for ligand/receptor complexes, such as fibroblast growth factor 1 (FGF1) with FGF receptors. (B) Diabetes and metabolic inflammation lead to increased shedding of proteoglycans from the ECM, either by cleaving the protein core or the attached GAG chains. Shed proteoglycans and GAG chains have been shown to engage with toll-like receptors (TLRs), thereby potentiating the inflammatory response via NF-κB downstream signaling. Proteoglycans and GAGs released in the circulation can therefore have systemic effects and could be used as biomarkers for metabolic disease (e.g., GPC4). (C) Membrane bound proteoglycans (e.g., syndecans or glypicans) are in involved in retention of immune cells by directly engaging with lectins on the surface of immune cells. Proteoglycans also regulate the accessibility of adhesion molecules such as ICAM-1 on the cell surface which are important for the attachment of leucocytes. (D) Proteoglycans mediate the interaction between other ECM components such as collagens and fibrinogen. Dysregulations in ECM deposition lead to the development of fibrosis, a common pathology associated with metabolic disease.