TSG-6 Inhibits Neutrophil Migration via Direct Interaction with the Chemokine CXCL8

Abstract

TNF-stimulated gene/protein-6 (TSG-6) is expressed by many different cell types in response to pro-inflammatory cytokines and plays an important role in the protection of tissues from the damaging consequences of acute inflammation. Recently, TSG-6 was identified as being largely responsible for the beneficial effects of multipotent mesenchymal stem cells, for example in the treatment of animal models of myocardial infarction and corneal injury/allogenic transplant. The protective effect of TSG-6 is due in part to its inhibition of neutrophil migration, but the mechanism(s) underlying this activity remain(s) unknown. Here we have shown that TSG-6 inhibits chemokine-stimulated trans-endothelial migration of neutrophils via a direct interaction (KD ~25 nM) between TSG-6 and the glycosaminoglycan-binding site of CXCL8, which antagonizes the association of CXCL8 with heparin. Furthermore, we found that TSG-6 impairs the binding of CXCL8 to cell surface glycosaminoglycans and the transport of CXCL8 across an endothelial cell monolayer. In vivo this could limit the formation of haptotactic gradients on endothelial heparan sulfate proteoglycans and, hence, integrin-mediated tight adhesion and migration. We further observed that TSG-6 suppresses CXCL8-mediated chemotaxis of neutrophils; this lower potency effect might be important at sites where there is high local expression of TSG-6. Thus, we have identified TSG-6 as a CXCL8-binding protein, making it the first soluble mammalian chemokine-binding protein to be described to date. We have also revealed a potential mechanism whereby TSG-6 mediates its anti-inflammatory and protective effects. This could inform the development of new treatments for inflammation in the context of disease or post transplantation.

A microscopic view on the renal endothelial glycocalyx

“…In part this is related to its gel-like physical properties. In addition, binding of TNF-stimulated gene 6 (TSG-6) to hyaluronan inhibits chemokine-stimulated transendothelial migration of neutrophils via a direct interaction between TSG-6 and the GAG-binding site of CXCL8 (23). However, during tissue injury and inflammatory processes hyaluronan can become depolymerized through oxidative stress and enzymatic cleavage by hyaluronidases.…”

Umbilical Cord Mesenchymal Stem Cells Suppress Host Rejection

“…Moreover, this same group was able to reduce the rejection of mouse allogeneic corneal transplants by intravenous administration of mesenchymal stem cells, which were shown to be trapped primarily in the lungs and to increase the levels of TSG6 (47). Dyer et al (48) have recently shown that free TSG-6 impairs both the binding of CXCL8 to cell surface GAGs and its transport across the endothelium, thereby impeding the CXCL8 gradient formation required for neutrophil chemotaxis and extravasation. Therefore, free TSG6 expressed by the UMSC could also be playing a role in suppressing the inflammatory response.…”

Immune modulation by virus-encoded secreted chemokine binding proteins

“…The crystal structure of evasins reveals novel protein folds (Deruaz et al, 2008;Dias et al, 2009). A recent report describes the first human secreted protein that inhibits chemokine activity (Dyer et al, 2014) and is unrelated to GPCRs. TNF-stimulated gene/protein-6 is secreted and inhibits neutrophil transendothelial migration, and was known to interact with several proteins (inter-alpha-inhibitor and thrombospondin-1) and GAGs.…”

“…Schistosoma mansoni (Smith et al, 2005) and ticks (Deruaz et al, 2008;Frauenschuh et al, 2007). More recently, a human soluble CKBP has been described (Dyer et al, 2014).…”