CD39 dictates cytoprotective effects of immune cell derived circulating microparticles in hepatic ischemia/reperfusion injury
Gastroenterology
Final Report Abstract
The original project plan focused on the analysis of CD39 expression and function on T cell derived microparticles (MP) in sterile liver inflammation. However, it turned out that the proposed method of conventional flow cytometry was not suited for MP analysis in this context for the following reasons: 1) small size of the MP, 2) low percentage of the T cell derived MP in the overall plasma MP population, and 3) strong interfering signal of unbound antibody. As an alternative approach, we developed an enzyme activity based assay that is independent of both particle size and antibodies. Using this new technique, we were surprised to see that a substantial portion of ectonucleotidase activity in the MP fraction of human plasma was not due to CD39 (NTPDase1), but a related enzyme, NTPDase3, that has not been studied extensively. In blood samples of patients with inflammatory bowel disease, as well as patients with nonalcoholic fatty liver disease (NAFLD), we observed a correlation between NTPDase3 activity and disease severity. This prompted me to further pursue the question what specific role NTPDase3 plays in liver disease. After completing the generation of a specific mouse line deficient for NTPDase3, I tested the effect of the gene deletion on severity of liver injury in different established animal models. Mice that lacked expression of NTPDase3 were found to be protected from experimental liver fibrosis when compared to wildtype mice. This result is surprising as CD39, a related enzyme that is well known to aggravate inflammation and liver disease, has opposite effects. The exact mechanism of the deleterious effect of NTPDase3 in liver fibrosis is the subject of my ongoing research. One possible mechanism is the polarization of intrahepatic macrophages towards a pro-inflammatory, anti-fibrotic phenotype by extracellular ATP that functions as a signaling molecule. Deletion of NTPDase3 could lead to higher ATP concentration and thus convey anti-fibrotic effects. A specific inhibitor against NTPDase3 is currently not available, but might be a potential therapeutic target for liver fibrosis in the future.
Publications
- (2014) Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma. Purinergic Signalling, 10, 611–618
Jiang ZG, Wu Y, Csizmadia E, Feldbrügge L, Enjyoji K, J Tigges, V Toxavidis, H Stephan, CE Müller, CE Müller, CJ McKnight, A Moss, SC Robson
(See online at https://doi.org/10.1007/s11302-014-9423-6)
