Syndecans in inflammation (original) (raw)
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Molecular and cellular mechanisms of syndecans in tissue injury and inflammation
Molecules and Cells, 2007
The syndecan family of heparan sulfate proteoglycans is expressed on the surface of all adherent cells. Syndecans interact with a wide variety of molecules, including growth factors, cytokines, proteinases, adhesion receptors and extracellular matrix components, through their heparan sulfate chains. Recent studies indicate that these interactions not only regulate key events in development and homeostasis, but also key mechanisms of the host inflammatory response. This review will focus on the molecular and cellular aspects of how syndecans modulate tissue injury and inflammation, and how syndecans affect the outcome of inflammatory diseases in vivo.
Syndecans in angiogenesis and endothelial cell biology
Biochemical Society Transactions, 2014
Syndecans are multifunctional heparan sulfate proteoglycans (HSPGs) with roles in cell adhesion, migration, receptor trafficking and growth-factor interactions and signalling. Studies using syndecan null animals have revealed limited roles for syndecans during development; however, under conditions of challenge or insult, several phenotypes have emerged. Angiogenesis is an important process both in development and in wound healing, but also in pathologies such as cancer and chronic inflammatory conditions. In the present paper, we summarize the main studies elucidating the role of syndecans in angiogenesis and their potential as novel therapeutic targets.
Syndecans as cell surface receptors: Unique structure equates with functional diversity
Matrix Biology, 2011
An increasing number of functions for syndecan cell surface heparan sulfate proteoglycans have been proposed over the last decade. Moreover, aberrant syndecan regulation has been found to play a critical role in multiple pathologies, including cancers, as well as wound healing and inflammation. As receptors, they have much in common with other molecules on the cell surface. Syndecans are type I transmembrane molecules with cytoplasmic domains that link to the actin cytoskeleton and can interact with a number of regulators. However, they are also highly complex by virtue of their external glycosaminoglycan chains, especially heparan sulfate. This heterodisperse polysaccharide has the potential to interact with many ligands from diverse protein families. Here, we relate the structural features of syndecans to some of their known functions.
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 2015
Syndecans are important cell surface proteoglycans with many functions; yet, they have not been studied to a very large extent in primary human endothelial cells. The purpose of this study was to investigate syndecan-4 expression in cultured human umbilical vein endothelial cells (HUVECs) and assess its role in inflammatory reactions and experimental wound healing. qRT-PCR analysis revealed that syndecan-3 and syndecan-4 were highly expressed in HUVECs, whereas the expression of syndecan-1 and -2 was low. HUVECs were cultured with the inflammatory mediators lipopolysaccharide (LPS) and interleukin 1β (IL-1β). As a result, syndecan-4 expression showed a rapid and strong increase. Syndecan-1 and -2 expressions decreased, whereas syndecan-3 was unaffected. Knockdown of syndecan-4 using siRNA resulted in changes in cellular morphology and focal adhesion sites, delayed wound healing and tube formation, and increased secretion of the pro-inflammatory and angiogenic chemokine, CXCL8. These data suggest functions for syndecan-4 in inflammatory reactions, wound healing and angiogenesis in primary human endothelial cells.
Isolation and functional analysis of syndecans
Methods in Extracellular Matrix Biology
Syndecans comprise a major family of cell surface heparan sulfate proteoglycans (HSPGs). Syndecans are composed of sulfated glycosaminoglycans (GAGs), heparan sulfate (HS) or both HS and chondroitin sulfate (CS), attached covalently to core proteins. Syndecans regulate many cellular processes, such as adhesion, proliferation, and migration. Syndecans bind and regulate molecules primarily through their HS chains, but do not bind to all HS/heparin-binding molecules. Furthermore, mice ablated for the syndecan-1 or-4 gene do not show major developmental abnormalities, but they do show striking pathological phenotypes when challenged with infectious or inflammatory stimuli and conditions, suggesting that certain functions of syndecans are specific and cannot be compensated for by other syndecans or other HSPGs. These observations underscore the physiological importance of syndecans and indicate a need to study the activities of isolated native syndecans to define their molecular and cellular functions, and to establish their biological significance. Here we describe methods to isolate syndecans and several assays to analyze their functions.
The signaling mechanisms of syndecan heparan sulfate proteoglycans
Current Opinion in Cell Biology, 2009
Syndecans are membrane proteins controlling cell proliferation, differentiation, adhesion and migration. Their extracellular domains bear versatile heparan sulphate chains that provide structural determinants for syndecans to function as co-receptors or activators for molecules like growth factors and constituents of the matrix. Syndecans also signal via their protein cores and their conserved transmembrane and cytoplasmic domains. The direct interactions and signalling cascades they support are becoming better characterized. These interactions are regulated by phosphorylation, induced clustering and shedding of the syndecan extracellular domain. Moreover evidence is emerging that syndecans concentrate in unconventional lipid domains and might govern novel vesicular trafficking pathways. Here we focus on recent findings that refine our understanding of the complex structure-function relationships of these cellular effectors.
Syndecan-1 as a regulator of chemokine function
TheScientificWorldJournal, 2003
Chemokines are a family of chemotactic cytokines that play critical roles in leukocyte recruitment to sites of inflammation. Characterized by the presence of conserved aminoterminal cysteine residues, these lowmolecular weight proteins signal through G-protein-coupled receptors with seven transmembrane domains[1,2]. Apart from their function in leukocyte recruitment, chemokines and their receptors have been ascribed roles in angiogenesis and tumor growth, infections, Th1 and Th2 responses, as well as the maturation and development of several leukocyte subpopulations[1]. Considering their fundamental role in orchestrating the inflammatory response, it is no surprise that a dysregulation of chemokine function is observed in a variety of pathological conditions, such as pulmonary fibrosis, hypersensitivity responses, chronic inflammation, and cancer[1,2,3,4]. For this reason, it is important to know how chemokine action is regulated in molecular detail, in order to develop more efficient therapies for diseases characterized by chemokine malfunction. Two recent papers shed more light on the regulation of chemokine function, uncovering a crucial role for the cell surface heparan sulfate (HS) proteoglycan syndecan-1 in the generation of chemokine gradients[5,6]. Using mice deficient in the matrix-metalloprotease matrilysin in an experimental model of lung fibrosis, Li et al.[5] observed an impaired transepithelial migration of neutrophils, which resulted in protection against the lethal effect of bleomycin-induced lung injury. They found that matrilysin sheds a complex of syndecan-1 and the CXC chemokine KC from the mucosal surface, which serves as a chemotactic gradient for neutrophils. Marshall et al.[6] used an in vitro model of transendothelial migration to demonstrate that syndecan-1 forms a chemotactic IL-8 gradient at the endothelial cell surface. An increase of constitutive syndecan-1/IL-8 complex shedding in the presence of a neutralizing antibody to plasminogen activator inhibitor-1 (PAI-1) resulted in an inhibition of transendothelial neutrophil migration. The syndecans are a family of cell surface heparan sulfate proteoglycans (HSPG), which act as adhesion molecules, modulators of growth factor function, and coreceptors in processes as diverse as morphogenesis, tissue repair, host defense, tumor development, and energy metabolism[7,8]. Protease-mediated cleavage of the intact syndecan ectodomains ("shedding") converts the cell-surface molecules into soluble effectors[9]. Increasing evidence suggests an important role for the syndecans in the
Syndecans as receptors and organizers of the extracellular matrix
Cell and Tissue Research, 2010
Syndecans are type I transmembrane proteins having a core protein modified with glycosaminoglycan chains, most commonly heparan sulphate. They are an ancient group of molecules, present in invertebrates and vertebrates. Among the plethora of molecules that can interact with heparan sulphate, the collagens and glycoproteins of the extracellular matrix are prominent. Frequently, they do so in conjunction with other receptors, most notably the integrins. For this reason, they are often referred to as “co-receptors”. However, just as with integrins, syndecans can interact with actin-associated proteins and signalling molecules, such as protein kinases. Some aspects of syndecan signalling are understood but much remains to be learned. The functions of syndecans in regulating cell adhesion and extracellular matrix assembly are described here. Evidence from null mice suggests that syndecans have roles in postnatal tissue repair, inflammation and tumour progression. Developmental deficits in lower vertebrates in which syndecans are eliminated are also informative and suggest that, in mammals, redundancy is a key issue.
Syndecan-2 downregulation impairs angiogenesis in human microvascular endothelial cells
Experimental Cell Research, 2009
Angiogenesis is a tightly regulated process in vertebrates that leads to the formation of new blood vessels from pre-existing vessels or by the recruitment of bone marrow-derived endothelial precursor cells . During embryogenesis, after stimulation by proangiogenic factors, such as VEGF or FGF, it contributes to the maturation of the vascular plexus. In adults, it is important in some physiologic conditions, such as wound healing or the reproductive cycle in females, although most of the time it is "switched off" by endogenous inhibitors, such as endostatin or angiostatin. Furthermore, its misregulation is the cause of many pathological situations, as it contributes to tumor development[2], diabetic retinopathy[3], rheumatoid arthritis[4], psoriasis , but also cardiovascular disorders[6] and obesity .