Natural killer T (NKT)-cell mediated tissue injury is modulated by CD39 in models of nonalcoholic fatty liver disease.
Final Report Abstract
The proposed project focused on the impact of CD39 expressing natural killer T (NKT) cells in experimental non-alcoholic steatohepatitis and liver fibrosis. The CD39/CD73 cascade serves anti-inflammatory and immunosuppressive functions, limiting the pro-inflammatory response of ATP and ultimately generating the anti-inflammatory, but pro-fibrotic adenosine. However, global deficient CD39 mice were not protected from fibrosis, when compared to wild type mice. Among the three purinergic enzymes (ADPase, 5`nucleotidase and adenosine deaminase) in extracellular purine metabolism we found that the first key step, degrading ATP into AMP, might not be of great importance in non-alcoholic fatty liver disease. Particularly, it turned out that the activity of the recently rediscovered macrophagederived enzyme adenosine deaminase 2 (ADA2), which converts extracellular adenosine to inosine, is strongly associated with the stage of liver fibrosis in humans. We noticed that ADA2 is strongly expressed in hepatic macrophages, particularly in the portal area. We hypothesized that infiltrative macrophage-derived ADA2 modulates the phenotype of surrounding hepatic macrophages in an autocrine and paracrine manner. To test the effect of ADA2 on macrophages, we treated human blood-derived macrophages with recombinant wild type ADA2 and found among others an increase of PDGF-BB expression, a key profibrotic factor in liver fibrosis. Notably, we also detected an up-regulation of PDGF-BB transcription in macrophages in response to low-dose ADA2 and the substrate adenosine, suggesting that enzyme activity is a significant factor to drive a pro-fibrotic phenotype. In summary, we conclude that infiltrative macrophages in the portal area express highly and secret ADA2, which modulates a pro-fibrotic response via changing the extracellular adenosine-inosine mileu. This finding underscores the importance of the ADA2 pathway in regulating macrophages polarization, which might be a promising target to treat liver fibrosis.
Publications
- Adenosinergic Signaling in Liver Fibrosis. Clin. Liver Dis. 2019;14:1–4
Tiwari‐Heckler S, Jiang ZG
(See online at https://doi.org/10.1002/cld.777)
