Purinergic signaling; Liver regeneration; NTPDase1/CD39; liver resection; natural killer cell; extracellular ATP; NTPDase
Graubardt Nadine, Fahrner René, Trochsler Markus, Keogh Adrian, Breu Karin, Furer Cynthia, Stroka Deborah, Robson Simon C, Slack Emma, Candinas Daniel, Beldi Guido (2013), Promotion of liver regeneration by natural killer cells in a murine model is dependent on extracellular adenosine triphosphate phosphohydrolysis., in Hepatology (Baltimore, Md.)
, 57(5), 1969-79.
Beldi Guido, Banz Yara, Kroemer Alexander, Sun Xiaofeng, Wu Yan, Graubardt Nadine, Rellstab Alyssa, Nowak Martina, Enjyoji Keiichi, Li Xian, Junger Wolfgang G., Candinas Daniel, Robson Simon C. (2010), Deletion of CD39 on Natural Killer Cells Attenuates Hepatic Ischemia/Reperfusion Injury in Mice, in HEPATOLOGY
, 51(5), 1702-1711.
BackgroundSurgery offers the only potential cure in many patients with primary or metastatic liver cancer. Extending the limits and improving safety of liver resection would allow more patients to benefit from surgery and to in-crease their survival. The prerequisite for successful and safe liver surgery is the optimal regeneration of the remaining hepatic tissue in order to fulfill the metabolic demands of the patient.Liver regeneration is closely coordinated by paracrine mechanisms. Natural killer (NK) cells are the dominant lymphocyte population in the human liver and have been shown to modulate hepatocellular regeneration and injury after partial liver resection in mice. However, mechanisms that regulate important NK cell functions such as cytotoxicity or cytokine secretion during liver regeneration remain unknown. Extracellular nucleotides such as ATP activate specific purinergic (P2) receptors that are present on a variety of immune cells including NK cells. Levels of extracellular ATP are regulated by cellular release and enzymatic hydrolysis by ectonucleotidases (mainly CD39/ENTPDase1). Preliminary results show a significant decrease of cytotoxicity of purified wild type NK cells by extracellular ATP. Pharmacological profiling reveals P2Y1 and P2Y2 as the receptors involved. Interestingly, cytotoxicity was increased in NK cells with genetic deletion of CD39 compared to wild type NK cells, possibly in response to P2Y receptor desensitization. In vivo, alterations of pericellular ATP levels in NK cells null for CD39 was associated with increased proliferation and decreased liver injury after partial liver resection. Aim: To explore the role of purinergic receptors on NK cell derived cytotoxicity in a mouse model of partial liver resection.Specific aims1. To determine the role of extracellular ATP on NK cell cytotoxicity in a model of partial liver resection. 2. To explore the specific role of P2Y receptor activation on NK cell cytotoxicity in vitro and in a model of partial liver resection. 3. To determine the presence of P2Y receptor desensitization in response to deletion of CD39.SignificanceAspects of innate immunity that contribute to liver injury and hepatocellular proliferation during liver regeneration will be investigated in this proposal. Future therapeutic options may result as nucleotides and its derivatives have already been synthesized as small and stable compounds. Their administration could potentially improve hepatic regeneration after major liver resection. This could, ultimately, allow to extend boarders of hepatic resection and to improve patient’s outcome for advanced primary and metastatic liver tumors.