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

• Applicant: Professor Dr. Markus P. Radsak
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2005 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 17136808

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.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1151: Immune and Metabolic Modulation Induced by Severe Tissue Trauma
• Participating Person: Professor Dr. Hansjörg Schild