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

Toll样受体(TLR)通过对微生物或病毒来源的保守结构的特异性识别，在中性粒细胞(PMN)对微生物病原体的天然免疫应答中发挥重要作用。TREM-1是最近发现的一种活化受体，表达于中性粒细胞上，在急性感染中起着至关重要的作用。TLR配体刺激后，TREM-1的表达上调。最近，我们和其他人证明了通过TREM-1和TLR同时刺激PMN导致中性粒细胞效应功能的协同激活，如脱颗粒和呼吸爆发，而TLR配体对PMN存活的抗凋亡作用被中和。除此之外，已证明TREM-1也以可溶形式释放，即在重症肺炎、败血症或内毒素血症等感染患者中释放，这表明TREM-1以可溶形式也可能具有生物学意义。然而，TREM-1作为脓毒症高危患者微生物感染的预后或早期诊断标记物的价值尚未被调查。我们建立了一种新的特异度TREM-1的酶联免疫吸附试验，能够检测患者血清中微微克量的可溶性TREM-1。在我们目前资助的项目(RA988/2-1/2)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，这些患者发生败血症并发症的风险很高。我们的目的是评估Strem-1的检测是否可以作为这些患者的有用的诊断或预后标志物。此外，我们有兴趣研究TREM-1和TLR介导的PMN在这些患者中的效应功能，以及这些功能在创伤患者中是否发生了变化。这些实验的结果可能有助于更好地理解为什么多发性创伤患者有如此高的严重感染风险，并可能有助于为这些患者开发新的诊断或治疗方法。我们希望通过上述实验扩展我们目前由DFG资助的项目，并将这一部分整合到DFG优先计划SPP1151中。

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.