The interaction of C-reactive protein (CRP) with the complement system in the pathogenesis, diagnosis and therapy of the post traumatic inflammatory response

• Applicants: Professor Dr. Steffen Ulrich Eisenhardt; Professor Dr. Markus Huber-Lang
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317175199

C-reactive protein (CRP) is a highly conserved pentameric protein. It is not only a marker, but also a mediator of inflammation. As part of the innate immune system it opsonizes bacteria and can regulate activation of the complement system. In trauma, as well as in septicaemia, uncontrolled activation of the complement system can lead to exacerbation of the inflammatory immune response leading to organ damage via activation of complement C5. This uncontrolled activation of the immune response can occur during the so called second-hit, that refers to increased tissue injury in secondary events after initial traumatic tissue injury. Controlling this inflammatory response is key to preventing its detrimental consequences.We have shown previously that localized dissociation of pentameric CRP to its single monomeric subunits represents a ubiquitious mechanism by which CRP regulates the inflammatory response in areas of inflammation. Blocking this dissociation step by a novel compound leads to markedly reduced inflammation. Our data suggest that initial increase of CRP after traumatic tissue injury might be a priming process for following events leading to increased localized CRP dissociation in the event of a following secondary injury. We therefore believe that CRP is a crucial causal factor in the second- hit response. However it remians unclear how the conformational change of CRP alters the modulating properties of CRP on the complement system. Here we aim to investigate the effects of the confomational change from pentameric to monomeric CRP on its effect on complement factors regarding the modulation and aggravation of an existing inflammatory event. We will investigate the pathomechanistic sequelae from complement activation to the differential activation of leukocyte subsets with emphasis on the interaction of CRP dissociation, complement activation and activation of monocyte subsets in order to taylor specific therapeutic approaches targeting the second-hit response. We will transfer our findings to an established animal model of the second-hit response in order to confirm the causal role of CRP dissociation in the pathology of the second-hit and to prove that targeting CRP dissociation is a suitable therapeutic approach to modulate and control the exacerbated inflammatory response in second-hit. In a clinical pilot study we will investigate CRP-dissociation products and their interaction with factors of the complement system as biomarkers with predictive value in polytrauma.

• DFG Programme: Research Grants