Entpd1, also known as CD39, is an ectonucleotidase that plays a crucial role in the purinergic signaling pathway. It is the rate-limiting enzyme in the cascade converting ADP/ATP to AMP, ultimately leading to the generation of immunosuppressive adenosine through the action of CD73 [1,2,3]. This pathway is significant in calibrating the immune response, shifting from a pro-inflammatory ATP-driven environment to an anti-inflammatory adenosine-induced milieu [2].

In various disease models, Entpd1 has shown diverse functions. In cancer, gene knockout models have provided evidence for the anticancer activity of CD39 inhibition. For example, in hepatic metastatic cancer models, Cd39 null vasculature or circulating Cd39 null bone marrow-derived cells strongly inhibited tumor growth, indicating that CD39 expression on regulatory T cells (Tregs) promotes tumor growth by suppressing natural killer (NK) cell activity [6]. In septic mouse models, CD39 -/- mice had higher levels of inflammatory cytokines and more pronounced liver injury compared to wild-type mice, suggesting that CD39 attenuates sepsis-associated liver injury by scavenging extracellular ATP [4]. In diabetic nephropathy models, inducing diabetes in Entpd1-null mice led to increased proteinuria, more severe glomerular sclerosis, and enhanced glomerular inflammation, showing that Entpd1 is a vascular protective factor in this disease [5].

In conclusion, Entpd1 is essential in regulating the purinergic signaling pathway, which has far-reaching impacts on immune responses and inflammation. Gene knockout mouse models have been instrumental in revealing its role in cancer, sepsis-induced liver injury, and diabetic nephropathy. These findings suggest that targeting Entpd1 could be a potential therapeutic strategy in these disease areas.

References:

1. Bastid, J, Cottalorda-Regairaz, A, Alberici, G, Eliaou, J-F, Bensussan, A. 2012. ENTPD1/CD39 is a promising therapeutic target in oncology. In Oncogene, 32, 1743-51. doi:10.1038/onc.2012.269. https://pubmed.ncbi.nlm.nih.gov/22751118/

2. Antonioli, Luca, Pacher, Pál, Vizi, E Sylvester, Haskó, György. 2013. CD39 and CD73 in immunity and inflammation. In Trends in molecular medicine, 19, 355-67. doi:10.1016/j.molmed.2013.03.005. https://pubmed.ncbi.nlm.nih.gov/23601906/

3. Timperi, Eleonora, Barnaba, Vincenzo. 2021. CD39 Regulation and Functions in T Cells. In International journal of molecular sciences, 22, . doi:10.3390/ijms22158068. https://pubmed.ncbi.nlm.nih.gov/34360833/

4. Savio, Luiz Eduardo Baggio, de Andrade Mello, Paola, Figliuolo, Vanessa R, Robson, Simon C, Coutinho-Silva, Robson. 2017. CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. In Journal of hepatology, 67, 716-726. doi:10.1016/j.jhep.2017.05.021. https://pubmed.ncbi.nlm.nih.gov/28554875/

5. Friedman, David J, Rennke, Helmut G, Csizmadia, Eva, Enjyoji, Keiichi, Robson, Simon C. 2007. The vascular ectonucleotidase ENTPD1 is a novel renoprotective factor in diabetic nephropathy. In Diabetes, 56, 2371-9. doi:. https://pubmed.ncbi.nlm.nih.gov/17473221/

6. Sun, Xiaofeng, Wu, Yan, Gao, Wenda, Murakami, Takashi, Robson, Simon C. 2010. CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. In Gastroenterology, 139, 1030-40. doi:10.1053/j.gastro.2010.05.007. https://pubmed.ncbi.nlm.nih.gov/20546740/