The role of the alarmin S100A8/A9 and its counter receptor TLR4/MD2 on platelets in the regulation of inflammation, glycocalyx integrity and vascular permeability during inflammation
The endothelial glycocalyx is a dynamic structure localized at the luminal side of the endothelium and plays a central role in the context of vascular permeability. Main components of the glycocalyx are membrane-bound proteoglycans and glycoproteins incorporating plasma- and endothelium-derived soluble components and is part of the endothelial barrier. Vascular inflammation leads to the degradation of the endothelial glycocalyx which is related to altered vascular permeability.
The activation of TLR2 and/or TLR4 expressing cells contributes to glycocalyx degradation. Vascular inflammation also induces the cleavage activity of the enzymes heparanase and hyaluronidase resulting in shedding of the glycocalyx components syndecan-1 and hyaluronic acid. Heparanase and hyaluronidase are also expressed and released by activated platelets and contribute further to the degradation of the endothelial glycocalyx and the subendothelial extracellular matrix. How neutrophil-derived S100A8/A9 affects NET formation and subsequently modulates the activation and participation of platelets in the leukocyte recruitment, the degradation of the glycocalyx, and vascular permeability increase is unknown and will be the subject for investigation within this project.