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Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease

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 CD...

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Main Authors: Tiwari-Heckler, Shilpa (Author) , Yee, Eric U. (Author) , Yalcin, Yusuf (Author) , Park, Jiwoon (Author) , Nguyen, Duc-Huy T. (Author) , Gao, Wenda (Author) , Csizmadia, Eva (Author) , Afdhal, Nezam (Author) , Mukamal, Kenneth J. (Author) , Robson, Simon C. (Author) , Lai, Michelle (Author) , Schwartz, Robert E. (Author) , Jiang, Z. Gordon (Author)
Format: Article (Journal)
Language:English
Published: 26 October 2021
In: Cell reports
Year: 2021, Volume: 37, Issue: 4, Pages: 1-20
ISSN:2211-1247
DOI:10.1016/j.celrep.2021.109897
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2021.109897
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S221112472101367X
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Author Notes:Shilpa Tiwari-Heckler, Eric U. Yee, Yusuf Yalcin, Jiwoon Park, Duc-Huy T. Nguyen, Wenda Gao, Eva Csizmadia, Nezam Afdhal, Kenneth J. Mukamal, Simon C. Robson, Michelle Lai, Robert E. Schwartz, Z. Gordon Jiang
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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.
Item Description:Gesehen am 13.12.2021
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2021.109897

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