Syndecans in chronic inflammatory and autoimmune diseases: Pathological insights and therapeutic opportunities

Abstract

Syndecans (SDCs) are a family of heparan sulfate proteoglycans (HSPGs) glycoproteins ubiquitously expressed on the cell surfaces and extracellular matrix of all mammalian tissues. There are four mammalian syndecans, SDC-1 thorough 4, which play a critical role in cell adhesion, migration, proliferation, differentiation, and angiogenesis through independent and growth factor mediated signaling. An altered expression of SDCs is often observed in autoimmune disorders, cancer, HIV infection, and many other pathological conditions. SDCs modulate disease progression by interacting with a diverse array of ligands, receptors, and other proteins, including extracellular matrix, glycoproteins, integrins, morphogens, and various growth factors and chemokines, along with their receptors and kinases. Specifically, SDCs present on cell surface can bind directly to chemokines to enhance their binding to receptors, downstream signaling, and migration. Alternatively, SDCs can be cleaved and shed to mediate negative regulation of chemokine and growth factor signaling pathways and ligand sequestration. Importantly, SDC shedding may be a biomarker of inflammation, especially in chronic inflammatory diseases. While the current therapies for cancer and several autoimmune disorders have revolutionized treatment outcomes, understanding the pathophysiological role of SDCs and the use of HSPG mimetic or antagonists on cytokine signaling networks may uncover potentially novel targeted therapeutic approaches. This review mainly summarizes the current findings on the role of individual SDCs in disease processes, mechanisms through which SDCs mediate their biological functions, and the possibility of targeting SDCs as future potential therapeutic approaches.

Keywords: autoimmune diseases; cancer; heparan sulfate proteoglycans; signaling pathways; syndecans; therapeutics.

FIGURE 1

Structural organization of Syndecans. A schematic view of syndecan core protein and glycosaminoglycan chains. SDC-1 and SDC-3 core proteins are larger than SDC-2 and SDC-4 and in addition to heparan sulfate chains they also bear CS. The GAG chains are substituted on core protein serine residues and have common tetrasaccharide units attached to two units of galactose (gal) and GlcA residue with alternating units of GlcNAc and uronic acids. The HS chains undergo modification by sulfonation at 6-O or 3-O (rarely), CS 6-O, or 4-O while uronic acids undergo epimerization to IdoA. The cytoplasmic domain contains highly conserved regions (C1 and C2) with interceding variable (V) regions