Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease
Year: 2021
Type: article
Abstract: Elevated circulating activity of adenosine deaminase 2 (ADA2) is associated with liver fibrosis in nonalcoholic fatty liver disease (NAFLD). In the liver of NAFLD patients, ADA2-positive portal macrophages are significantly associated with the degree of liver fibrosis. These liver macrophages are CD14- and CD16-positive and co-express chemokine receptors CCR2, CCR5, and CXCR3, indicating infiltrative monocyte origin. Human circulatory monocytes release ADA2 upon macrophage differentiation in vitro. When stimulated by recombinant human ADA2 (rhADA2), human monocyte-derived macrophages demonstrate upregulation of pro-inflammatory and pro-fibrotic genes, including PDGF-B, a key pro-fibrotic cytokine. This PDGF-B upregulation is reproduced by inosine, the enzymatic product of ADA2, but not adenosine, and is abolished by E359N, a loss-of-function mutation in ADA2. Finally, rhADA2 also stimulates PDGF-B production from Kupffer cells in primary human liver spheroids. Together, these data suggest that infiltrative monocytes promote fibrogenesis in NAFLD via ADA2-mediated autocrine/paracrine signaling culminating in enhanced PDGF-B production.
Source: Cell Reports
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: American Association for the Study of Liver Diseases, Irma T. Hirschl Trust, American College of Gastroenterology, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Adenosine deaminase 2 regulates macrophage phenotype and liver fibrosis in nonalcoholic fatty liver disease, Modeling alcohol toxicity in human hepatocytes, Optimization of the engineered 3D hepatic microenvironment enhances pluripotent stem cell derived hepatocyte, Engineering Inhibitory Antibodies to Ectoenzymes for Cancer Treatment, G6352056546, Non-invasive evaluation of Non-alcoholic Steatohepatitis, CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE, Modeling Hepatoblastoma using pluripotent stem cell derived hepatocyte-like cells, G8899348984, Genetic Viral and Host Adaptations to Breach Species Barriers of HCV
OpenAlex ID: W3210180537