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

Alarmin S100A8/A9 对肺部炎症期间血小板和中性粒细胞反应的影响

• 批准号: 427775266
• 负责人: Professor Dr. Jan Rossaint
• 金额: --
• 依托单位: Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/427775266?language=en
• 关键词: Effects; Alarmin; S100A8; A9; Platelet

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.

炎症，例如由于侵入的外源性病原体释放病原体相关分子模式（PAMP）分子或组织创伤、缺血/再灌注或化学损伤，导致释放损伤相关分子模式（DAMP）分子，也称为警报素。这标志着血管炎症和中性粒细胞募集到炎症部位的开始，以及有效免疫应答的产生。除了嗜中性粒细胞，血小板也积极参与炎症过程的发病机制，并可附着于活化的内皮细胞。促炎DAMP（或alarmin）分子S100 A8/A9（钙卫蛋白，Mrp 8/14）在骨髓来源的细胞（即嗜中性粒细胞和单核细胞）中高度表达。S100 A8/A9异源二聚体已被鉴定为在许多炎症性疾病期间的关键参与者，并且属于Ca 2+结合蛋白的S100家族。在被动或主动释放S100 A8/A9后，该分子主要通过模式识别受体Toll样受体4（TLR 4）发挥其效应子功能。TLR 4在多种细胞上表达，但也在血小板上表达。在S100 A8/A9的被动或主动分泌期间，这些胞质蛋白作为蛋白质组分被释放，所述蛋白质组分缠绕在形成的嗜中性粒细胞胞外陷阱（NET）的染色质纤维内，并且通常诱导广谱促炎作用。中性粒细胞与血小板的相互作用对于NET的形成是必不可少的，NET是许多炎症事件中的一个组成部分。NET从血流中清除循环细菌，并可能引起血管通透性增加。内皮糖萼是位于内皮细胞腔侧的动态结构，在血管通透性方面起着核心作用。糖萼的主要成分是膜结合蛋白聚糖和糖蛋白，结合血浆和内皮源性可溶性成分，是内皮屏障的一部分。血管炎症导致内皮糖萼的降解，这与血管通透性的改变有关。在其他受体中，表达TLR 2和/或TLR 4的细胞的活化有助于糖萼降解。血管炎症还诱导酶类肝素酶和透明质酸酶的切割活性，导致糖萼组分多配体蛋白聚糖-1和透明质酸的脱落。乙酰肝素酶和透明质酸酶也由活化的血小板表达和释放，并进一步促进内皮糖萼和内皮下细胞外基质的降解。嗜中性粒细胞衍生的S100 A8/A9如何影响NET形成并随后调节血小板活化和参与白细胞募集、糖萼降解以及髓源性抑制细胞（MDSC）的扩增和/或活化尚不清楚，将成为本项目提案中研究的主题。