A7: Role of myeloid-derived suppressor cells (MDSCs) in trauma- induced septic lung injury
PI: G. Strauß
Acute lung injury (ALI) is a life threatening disease induced either by direct injury, indirectly by sepsis or a combination of both. In the first funding period we could show that isolated blunt chest trauma (TxT) resulted in the local and systemic induction of MDSCs, an immature population of heterogeneous myeloid cells strongly regulating innate and adaptive immunity. MDSCs dampened antigen-mediated T cell proliferation in vitro and in vivo, however, exhibited immunostimulatory functions by attenuating the systemic pro-inflammatory response and supporting Th1 functions. Adoptive transfer of in vitro-generated MDSCs in TxT mice even increased splenic lymphocyte numbers, T cell survival and antigen-specific T cell proliferation. Therefore, in the second period we will determine the role of MDSCs in trauma-induced septic lung injury using the combined model of TxT and cecal ligation and puncture (CLP-induced sepsis) differing from isolated TxT by enhanced inflammation and long-lasting immunparalysis. Usage of different ALI models will indicate whether severity of the traumatic insult and type and strength of the inflammatory response is associated with differences in MDSC induction and function and their subsequent effect on the innate and adaptive immune response. Most importantly, we will define whether and how adoptively transferred in vitro-generated MDSCs modulate the trauma-induced innate immunity by analyzing pro-inflammatory cytokine release, complement activation and barrier dysfunction. Adoptive transfer of MDSCs will further indicate whether MDSCs exhibit long-lasting immunostimulatory effects on the adaptive immune response by maintaining lymphocyte survival, functions and antigen presentation and thereby counteracting or attenuating posttraumatic immune suppression and supporting immune homeostasis.