Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease
| العنوان: | Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease |
|---|---|
| المؤلفون: | Kenneth J. Mukamal, Jiwoon Park, Yusuf Yalcin, Duc-Huy T. Nguyen, Eva Csizmadia, Robert E. Schwartz, Nezam H. Afdhal, Z. Gordon Jiang, Simon C. Robson, Michelle Lai, Shilpa Tiwari-Heckler, Wenda Gao, Eric U. Yee |
| المصدر: | Cell reports |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, CCR2, Adenosine Deaminase, Kupffer Cells, CD14, medicine.medical_treatment, Monocytes, Article, General Biochemistry, Genetics and Molecular Biology, Chemokine receptor, Non-alcoholic Fatty Liver Disease, Paracrine Communication, Nonalcoholic fatty liver disease, medicine, Humans, Autocrine signalling, Aged, Chemistry, Monocyte, Proto-Oncogene Proteins c-sis, Middle Aged, medicine.disease, Adenosine, Autocrine Communication, medicine.anatomical_structure, Cytokine, Liver, Cancer research, Intercellular Signaling Peptides and Proteins, Female, medicine.drug |
| الوصف: | SUMMARY 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. Graphical Abstract In brief Tiwari-Heckler et al. find that infiltrative monocytes release ADA2 in NAFLD, which in turn promotes a pro-inflammatory and pro-fibrotic differentiation of monocyte-derived macrophages and Kupffer cells. This activity is at least in part dependent upon the deaminase activity of ADA2, inosine, the enzymatic product, and the production of PDGF-B. |
| تدمد: | 2211-1247 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::470cd4249861dce5b1fae85a02a8f4a4 https://doi.org/10.1016/j.celrep.2021.109897 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....470cd4249861dce5b1fae85a02a8f4a4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22111247 |
|---|