Thrombocytopoiesis in Diabetes: Role of Damage Associated Molecular Patterns

血小板在动脉粥样硬化的发生和发展中起重要作用， 动脉粥样硬化血栓形成并发症尽管标准抗血小板药物降低了动脉粥样硬化血栓形成的风险， 尽管它们在高风险患者中具有预防并发症的作用，但它们在糖尿病（DM）受试者中不是非常有效。的原因 这一点尚不清楚，但可能是由于网状血小板（RP）的产生/释放增加， 骨髓（BM）。RP不成熟，体积较大，反应过度，对标准抗- 血小板药物血小板生成受血小板生成素（TPO）及其受体c- MPL，其存在于几种BM祖细胞上。而TPO由BM基质组成性产生， 细胞和肾脏，肝脏在炎症期间成为它们的主要来源，其中肝脏TPO产生 通过白细胞介素-6（IL-6）的作用而增加。我们的初步数据表明高血糖 通过涉及嗜中性粒细胞衍生的S100 A8/A9的机制增强血小板生物合成， 相关分子模式（DAMP）复合物、枯否细胞（KC）衍生的白细胞介素-6（IL-6）和肝TPO。 对人类的研究也发现血浆S100 A8/A9、IL-6和血小板聚集之间呈正相关。 聚合来最重要的是，血清S100 A8/A9的增加与抗血小板作用的降低有关。 阿司匹林基于我们的初步数据和临床证据，我们假设高血糖诱导的 肝KCs产生IL-6可升高血浆TPO并启动血小板生成， 血液中RP的比例。新形成的RPs具有高反应性， 相互作用并导致动脉粥样硬化血栓形成并发症。为了验证这个假设，我们首先 研究葡萄糖如何增强糖尿病中RP的产生。我们将具体识别相声 通过控制血糖、中性粒细胞、血清S100 A8/A9和血清白细胞介素10（IL-10）， KCs中的IL-4/IL-6信号传导，并研究这些操作如何影响RP的产生。第二，我们将评估 通过进行各种血小板功能测定，研究糖尿病患者RP的致动脉粥样硬化和血栓形成特性 在小鼠和2型糖尿病受试者中均如此。这些研究的结果将对当前的 抗血小板治疗，特别是在DM受试者中，因为发现新靶点的潜力很大， 治疗心血管疾病。

Platelets play an important role in the initiation and propagation of atherosclerosis and, more so, in the ensuing atherothrombotic complications. Although the standard antiplatelet drugs reduce the risk of atherothrombotic complications in high-risk patients, they are not very effective in diabetes mellitus (DM) subjects. The reasons for this remains unclear but likely due to increased production/release of reticulated platelets (RP) from the bone marrow (BM). The RPs are immature, larger in size, hyperreactive, and less responsive to standard anti- platelet drugs. Platelet production is tightly regulated by the hormone thrombopoietin (TPO) and its receptor, c- MPL, which is found on several BM progenitor cells. While TPO is constitutively produced from BM stromal cells and the kidney, the liver becomes their major source during inflammation where hepatic TPO production is increased through the actions of interleukin-6 (IL-6). Our preliminary data suggests that hyperglycemia enhances platelet biogenesis via mechanisms that involve neutrophil-derived S100A8/A9, a Damage Associated Molecular Pattern (DAMP) complex, Kupffer cell (KC)-derived interleukin-6 (IL-6), and hepatic TPO. Studies in humans have also found a positive correlation between plasma S100A8/A9, IL-6, and platelet aggregation. Most importantly increased serum S100A8/A9 is associated with reduced anti-platelet effects of aspirin. Based on our preliminary data and the clinical evidence, we hypothesize that hyperglycemia-induced IL-6 production from hepatic KCs elevates plasma TPO and initiate thrombocytopoiesis resulting in higher proportion of RPs in the blood. The newly formed RPs, being hyperreactive, enhance platelet-leukocyte interactions and contribute to atherothrombotic complications. In order to test this hypothesis, firstly, we will examine how glucose enhances the production of RPs in diabetes. We will specifically identify the cross talk between circulating neutrophils and KCs by manipulating blood glucose, neutrophils, serum S100A8/A9 and RAGE/IL6 signaling in KCs and study how these manipulations affect RP production. Secondly, we will assess the atherogenic and thrombogenic properties of RPs in diabetes by performing various platelet function assays both in mice and type 2 DM subjects. The findings from these studies will have a broader impact on the current anti-platelet therapy particularly in DM subjects as there is a great potential for discovery of novel targets to treat cardiovascular disease.