Activation mechanisms by TREM-1 and it´s significance in immunomodulation post trauma

所谓的Toll样受体（TLR）通过特异性识别微生物或病毒来源的保守结构，在多形核中性粒细胞（PMN）激活针对微生物病原体的先天性免疫应答中起重要作用。TREM-1是最近描述的在PMN上表达的活化受体，在急性感染中具有至关重要的作用。TREM-1的表达在TLR配体刺激后上调。最近，我们和其他人能够证明，通过TREM-1和TLR同时刺激PMN导致协同激活中性粒细胞效应功能，如脱粒和呼吸爆发，而TLR配体对PMN存活的抗凋亡作用被中和。除此之外，已经证明TREM-1也以可溶形式释放，即在患有感染如严重肺炎、败血症或内毒素血症的患者中，这表明可溶形式的TREM-1也可能具有生物学意义。然而，尚未研究TREM-1作为脓毒症高风险患者中微生物感染的预后或早期诊断标志物的价值。我们已经开发并建立了一种新的TREM-1特异性ELISA，该ELISA能够检测患者血清中皮克量的可溶性TREM- 1。在我们目前资助的项目（Ra 988/2-1/2）的扩展中，我们计划分析急性创伤后患者的血清样本。众所周知，这些患者发生脓毒性并发症的风险很高。我们的目的是评估斯特雷姆- 1的检测是否可以作为这些患者的有用诊断或预后标志物。此外，我们有兴趣研究TREM-1和TLR介导的效应功能的中性粒细胞在这些患者和这些功能是否改变创伤患者。从这些实验中获得的结果可能有助于更好地理解为什么多发性创伤患者严重感染的风险如此之高，并可能有助于为这些患者开发新的诊断或治疗手段。我们希望通过上述实验扩展我们目前DFG资助的项目，并将这一部分纳入DFG优先计划SPP 1151。

So called Toll-like receptors (TLR) play an important role in the activation of the innate immune response against microbial pathogens by polymorphonuclear neutrophils (PMN) by the specific recognition of conserved structures of microbial or viral origin. TREM-1 is a recently described activating receptor expressed on PMN with a crucial importance in acute infections. The expression of TREM-1 is up-regulated after stimulation with TLR ligands. Recently, we and other were able to demonstrate that the simultaneous stimulation of PMN via TREM-1 and TLR leads to the synergistic activation of neutrophil effector functions like degranulation and respiratory burst, while the antiapoptotic effects of TLR ligands on PMN survival are neutralized. Beyond this it has been demonstrated that TREM-1 is also released in a soluble form, i.e. in patients with infections like severe pneumonia, sepsis or endotoxemia suggesting that TREM-1 in a soluble form might also be of biological significance. However, the value of TREM-1 as a prognostic or early diagnostic marker for microbial infections in patients high at risk of developing sepsis has not yet been investigated. We have developed and established a new TREM-1 specific ELISA that is able to detect picogramm amounts of soluble TREM- 1 in sera of patients. In extension of our currently funded project (Ra988/2-1/2), we are planning to analyze serum samples from patients post acute traumatic injuries. These patients are well known to be at high risk of developing septic complications. Our aim is to evaluate whether the detection of sTREM- 1 might serve as a useful diagnostic or prognostic marker in these patients. In addition, we are interested to study TREM-1 and TLR mediated effector functions of PMN in these patients and whether these functions are altered in trauma patients. The results obtained from these experiments might contribute to a better understanding of why poly trauma patients are so high at risk of severe infections and might help to develop new diagnostic or therapeutic means for these patients. We would like to extend our currently DFG-funded project by the experiments mentioned above and integrate this part into the DFG priority program SPP1151.