Role of RGM-A-Neogenin Axis on the Control of Inflammation-Resolution Programs during Liver I/R Injury

• Applicant: Professorin Dr. Valbona Mirakaj
• Subject Area: Anaesthesiology
• Term: from 2015 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268381366

Clinical conditions such as tissue resection, transplantation surgery, or hemorrhagic shock are critical causes of liver dysfunction and hepatic failure. Ischemia/reperfusion (I/R) is the main source of liver damage during these events and contributes to significant morbidity and mortality. A hallmark of the evolution of hepatic I/R injury is the recruitment of activated neutrophils into the affected tissue and the following defective inflammation-resolution. The prompt elimination of the disposed leukocytes is essential for the affected tissues to return to homeostasis and complete resolution of inflammation. This resolution of inflammation is an active process that ideally results in reconstituted organ function. Beside the resolution of inflammation, liver tissue regeneration following I/R injury has been strongly linked to the final outcomes of patients subjected to liver surgery. Recent work has identified neuronal guidance cues originally identified in the nervous system to hold additional function in the immune system on the control of acute inflammation. The repulsive guidance protein A (RGM-A) is one of these proteins and in previous work we were able to demonstrate its impact on the initiation of acute inflammation. In pilot experiments we found that RGM-A and its target receptor Neogenin are actively involved into the hepatic injury controlling the infiltration of leukocytes, modifying the production of pro-inflammatory cytokines and contributing to phagocytosis of apoptotic neutrophils. The aim of this proposal is to elucidate the effect of the RGM-A-Neogenin axis on the resolution/regeneration programs during hepatic I/R injury. A further understanding of the link between the neuronal guidance protein system and the hepatic inflammation represents a major opportunity to address a deficit in our understanding of pathways that can promote resolution and to identify new potential therapeutic targets for the future.

• DFG Programme: Research Grants