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Purinergic regulation of inflammation in liver fibrosis by ecto-nucleoside triphosphate diphosphohydrolase-3 (ENTPD3)

Subject Area General and Visceral Surgery
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 412957338
 
Final Report Year 2023

Final Report Abstract

Current challenges in liver fibrosis research include the specification of non-invasive biomarkers and the definition of targets for new treatments. Macrophages have evolved as crucial and versatile specialists in liver inflammation, immunity, fibrosis, and tissue repair. To comprehend their roles in liver fibrosis it is necessary to analyze them in the context of their specific microenvironment. Macrophages are known to express a diverse set of ecto-enzymes and purinergic receptors through which they are driven to diverse phenotypes and also influence surrounding cells. Purinergic signalling, transmitted by extracellular ATP, ADP, and adenosine through P1 and P2 receptors, shapes local stress responses. ATP can ignite inflammation via P2 receptors, such as P2X7, while the effects of adenosine through P1 receptors, dampen inflammation. Ecto-enzymes like CD39, ENTPD3 and 5’NT hydrolyze ATP and generate adenosine, promoting an immunoregulatory extracellular micro-milieu. ENTPD3, situated on nerve cells and also previously described on macrophages and hepatic stellate cells, is presumed to modulate local inflammation and tissue regeneration by eliminating extracellular ATP and ADP, similar to CD39. Our preliminary work with Entpd3 null mice suggested a deleterious role in liver fibrosis. Our hypothesis was that ENTPD3 amplifies adenosine signalling, inducing macrophages to release pro-fibrogenic molecules and activate hepatic stellate cells, possibly involving ENTPD3-carrying microparticles. The outcomes of our in vivo experiments with Entpd3 null mice failed to corroborate our initial anticipation of its profibrogenic characteristics. Furthermore, our in vitro studies revealed minimal ENTPD3 expression within differentiated murine M1 and M2 macrophages, with human macrophages showing some expression but again no differentiation between M1 and M2 phenotypes. In addition, hepatic ENTPD3 expression exhibited no correlation with fibrosis stages. Collectively, these findings compel us to reassess our earlier conjectures about the impact of ENTPD3 on liver fibrosis, suggesting that it may have been overestimated based on prior studies. Consequently, we opted not to proceed with further animal experiments originally planned for this project. Nevertheless, during the analysis of our clinical specimens, focusing on liver tumors that were prevalent in our patient cohort, we have discovered divergences in ENTPD expression within immune cell subsets across tissue, (metastastic) tumor microenvironment, and blood. These expression patterns seem to be connected with tumor stage and metastasis. CD39 has already been recognized as an immune checkpoint, relevant to tumor immune evasion, but the role of ENTPD3 has not been explored in detail. These findings are currently followed up in a new study.

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