04 Apr 2016 - TSG-6 is a pleotropic regulator of chemokine-GAG interactions

Copyright © Wellcome trust centre for Cell-Matrix Research

We have discovered that in addition to CCL5, CXCL8 and CXCL11, TSG-6 interacts with at least 7 other chemokines (i.e. CCL2, CCL7, CCL19, CCL21, CCL27, CXCL4, and CXCL12) including those involved in both homeostatic and inflammatory functions. TSG-6 interacts (via its Link module) with the GAG-binding site on the chemokines, thereby inhibiting the binding of chemokines to GAGs and their presentation on endothelial cells; TSG-6 also inhibits the binding of chemokines to collagen, providing another mechanism by which it can modulate chemokine activity in the matrix.

Chemokines play a critical role in directing immune cell recruitment by signalling through chemokine receptors that are differentially expressed on the surfaces of white blood cells. Importantly chemokines interact with the glycosaminoglycan (GAG) chains of proteoglycans present on blood vessel endothelia and in the matrix forming chemotactic gradients that guide migration of different leukocyte subsets during immune homeostasis and in the context of inflammation/infection. Previously we showed that TSG-6, a secreted inflammation-associated protein, interacts with the chemokines CCL5, CXCL8 and CXCL11 and inhibits CXCL8-mediated neutrophil trans-endothelial migration.

Importance: This research reveals that TSG-6 is a broad-spectrum chemokine-binding protein, which may have an important role in modulating the migration of a wide range of leukocyte subsets in the context of inflammation and immune homeostasis, i.e. in those tissues where it is constitutively expressed. These novel interactions likely underpin TSG-6’s tissue protective and anti-inflammatory functions, which we are aiming to harness for the treatment of musculoskeletal disease.

Reference:  Dyer, D.P., Salanga, C.L., Johns, S.C., Valdambrini, E., Fuster, M.L., Milner, C.M.*, Day, A.J.* and Handel, T.M.* (2016) The anti-inflammatory protein TSG-6 regulates chemokine function by inhibiting chemokine-glycosaminoglycan interactions. J Biol Chem. 291, 12627-40. PubMed *Co-corresponding authors.