CD39 dictates cytoprotective effects of immune cell derived circulating microparticles in hepatic ischemia/reperfusion injury

• Applicant: Privatdozentin Dr. Linda Feldbrügge
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 248345400

Ischemia/reperfusion injury (IRI) is a central process in liver transplantation and major liver resection. Bioactive substances are released by liver cells damaged by ischemia. During reperfusion, further cell injury is caused by a massive activation of inflammation. Central players of this lasting inflammatory process are CD4+ T helper cells. T regulatory cells (Tregs) are a subset of CD4+ T cells that inhibit T helper cells in inflammatory conditions such as autoimmune diseases, tumor immunity and transplant rejection. They are assumed to have a protective effect in liver IRI as well. T helper 17 cells (Th 17) are also a CD4+ T cell subset that originate from the same precursor cells as Tregs but have pro-inflammatory functions. Nucleotides like adenosine triphosphate (ATP), adenosine diphosphate (ADP) and derived nucleosides like adenosine serve as purinergic signal transmitters in basic physiological processes such as inflammation, coagulation and tissue regeneration. While ATP has mainly pro-inflammatory properties, the effects of its derivate adenosine are mostly anti-inflammatory. CD39 is an ectonucleotidase on the surface of endothelial and immune cells that regulates purinergic signaling by ATP/ADP phosphohydrolysis, resulting in increased levels of adenosine. Expression of CD39 has been shown to have a cytoprotective effect in hepatic IRI and is found on the surface of Tregs as well as a regulatory subset of Th17. Microparticles (MP) are small vesicles (<1,0 µm) derived from cell membranes and have been shown to be involved as mediators in intercellular cross-talk. CD39+ MP have been described that exert immuno-regulatory effects. We propose the presence of both Th17 and Treg derived MP in hepatic IRI that have immuno-regulatory effects on liver cells, dependent on their CD39 expression. In the proposed project IRI will be induced in the livers of wild type and CD39null mice to study MP and their interactions with liver and immune cells. In a further step Treg derived and Th17 derived CD39+ MP will be isolated and administered to mice before the induction of IRI to examine their effects on liver injury.The immuno-regulatory CD39+ MP that are examined in this study may in the future be used as important biomarkers and possibly considered as an alternative to cell therapy.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Simon Christopher Robson, Ph.D.