Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice

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. Hepatology, 51(5), pp. 1702-1711. Hoboken, N.J.: Wiley Interscience 10.1002/hep.23510

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Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. CONCLUSION: We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology

UniBE Contributor:

Beldi, Guido; Banz Wälti, Yara; Graubardt, Nadine and Candinas, Daniel

ISSN:

0270-9139

Publisher:

Wiley Interscience

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:07

Last Modified:

03 May 2014 02:49

Publisher DOI:

10.1002/hep.23510

PubMed ID:

20146261

Web of Science ID:

000277261400028

URI:

https://boris.unibe.ch/id/eprint/64 (FactScience: 194562)

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