Effects of the Alarmin S100A8/A9 on the Platelet and Neutrophil Response during Pulmonary Inflammation

炎症，例如由于外来病原体释放病原体相关分子模式(PAMPs)分子或组织创伤、缺血/再灌注或化学损伤而导致的损伤相关分子模式(DAMPS)分子的释放，也称为警报。这标志着血管炎症和中性粒细胞重新聚集到炎症部位，并产生有效的免疫反应。除了中性粒细胞外，血小板也积极参与炎症过程的发病过程，并能附着到激活的内皮细胞上。促炎症因子分子S100A8/A9(钙保护素，MRP8/14)高表达于髓系细胞，即中性粒细胞和单核细胞。S100A8/A9异源二聚体在许多炎症性疾病中起关键作用，属于S100钙结合蛋白家族。在被动或主动释放S100A8/A9后，该分子主要通过模式识别受体Toll样受体4(TLR4)发挥效应作用。TLR4在多种细胞上表达，也在血小板上表达。在S100A8/A9的被动或主动分泌过程中，这些胞浆蛋白以蛋白质组分的形式被释放，这些蛋白质组分缠绕在形成的中性粒细胞外陷阱(Net)的染色质纤维中，通常会诱导广泛的促炎作用。中性粒细胞与血小板的相互作用对Net的形成至关重要，Net是许多炎症事件中不可或缺的事件。蚊帐清除血液中的循环细菌，并可能导致血管通透性增加。内皮细胞糖萼是一种动态结构，定位于内皮细胞的管腔一侧，在血管通透性方面起着中心作用。糖萼的主要成分是膜结合的蛋白多糖和含有血浆和内皮来源的可溶性成分的糖蛋白，是内皮屏障的一部分。血管炎症导致内皮细胞糖基化，这与血管通透性改变有关。在其他受体中，表达TLR2和/或TLR4的细胞的激活有助于糖基化降解。血管炎症还会导致乙酰肝素酶和透明质酸酶的裂解活性，导致糖基化产物Syndecan-1和透明质酸的脱落。乙酰肝素酶和透明质酸酶也被激活的血小板表达和释放，并进一步促进内皮细胞糖萼和内皮下细胞外基质的降解。中性粒细胞来源的S100A8/A9如何影响净形成，并随后调节血小板在白细胞募集、糖萼降解以及髓系来源的抑制细胞(MDSCs)的扩张和/或激活中的激活和激活，目前尚不清楚，将在本项目提案中进行研究。

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.