KFO 342 - P5: Effects of the Alarmin S100A8/A9 on the Platelet and Neutrophil Response during Pulmonary Inflammation

Basic data for this project

Description

Inflammation, e.g. due to invading exogenous pathogens releasing pathogens associated molecular pattern (PAMPs) molecules or tissue trauma, ischemia/reperfusion or chemical injuries, leads to the release of damage-associated molecular pattern (DAMPs) molecules, also known as alarmins. This marks the beginning of vascular inflammation and neutrophil recruitment to sites of inflammation and the generation of an effective immune response. Besides neutrophils, platelets are also actively involved in the pathogenesis of inflammatory processes and can attach to activated endothelial cells. The pro-inflammatory DAMP (or alarmin) molecule S100A8/A9 (calprotectin, Mrp8/14) is highly expressed in cells of myeloid origin, namely neutrophils and monocytes. The S100A8/A9 heterodimer has been identified to be a critical player during many inflammatory disorders and belongs to the S100 family of Ca2+ binding proteins. After passive or active release of S100A8/A9, the molecule exerts its effector functions mostly via the pattern recognition receptor Toll-like receptor 4 (TLR4). TLR4 is expressed on a variety of cells, but also on platelets. During passive or active secretion of S100A8/A9, these cytosolic proteins are released as protein components entangled within the chromatin fibers of formed neutrophil extracellular traps (NETs) and in general induces a broad spectrum of pro-inflammatory effects. The interaction of neutrophils with platelets is essential for the formation of NETs, which are an integral event during many inflammatory events. NETs remove circulating bacteria from the bloodstream and may induce an increased vascular permeability. 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. Among other receptors, 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 the expansion and/or activation of myeloid-derived suppressor cells (MDSCs) is unknown and will be the subject for investigation within this project proposal.