Inflammation

Introduction

The research of my group focuses on the mechanism on how DAMPs are released, on the regulation of this process with a special focus on the role of plasma proteins herein, the identification of the cellular source of the DAMPs, and the systemic biological effects of the released DAMPs. 

Upon cell damage and cell death molecular structures, so-called damage-associated molecular pattern (DAMPs) are released into the circulation and induce a systemic inflammatory response by ligation of pattern recognition receptors (PRR). DAMPs released from nucleated cells include- among others- extra-cellular (cell-free) DNA, DNA-binding proteins (e.g. Histones, HMGB-1) and heme. DAMPs released from erythrocytes comprise hemoglobin, iron and heme, respectively. Extracellular DNA, e.g nucleosomes, and HMGB1 have been demonstrated to induce an inflammatory response via Toll-like receptor (TLR) 9 and histones via TLR2 and TLR4, respectively.

Heme is cytotoxic through the formation of highly active reactive oxygen species (ROS), an effect that is - in part - dependent on TLR4 and induction of the NFkappaB pathway. Complement activation upon damage of nucleated and non-nucleated cells propagate the inflammatory response induced by DAMPs and may lead by itself to cell destruction.

DAMPs may have detrimental effects by inducing a systemic inflammation resulting in fatality. In addition, the systemic inflammation may also facilitate and perpetuate (uncontrolled) activation of the adaptive immune response. Therefore the organism has multiple “self-defense” strategies to neutralize the potential fatal effects of DAMPs. These strategies include a tight regulation of DAMP release and the presence of systemic inhibitors (e.g. plasma proteins) to neutralize the toxic effects of DAMPs.

The last years it became evident that DAMPs may play significant role in the inflammatory processes occurring in hematological malignancies, e.g. graft versus host disease (GvHD) and neutropenic fever, as well as in benign hematological diseases, such as sickle cell disease, paroxysomal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA).

 

Medical needs:

Funding

  • ViroPharma
  • PPOC, internal funding (in competition), various projects
  • PPOP, internal funding (in competition)
  • TSN/AMR

Our research