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

Cell Rep. 2021 Oct 26;37(4):109897. doi: 10.1016/j.celrep.2021.109897.


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.

Keywords: Kupffer cells; Nonalcoholic fatty liver disease; adenosine deaminase 2; cat eye syndrome chromosome region 1; liver fibrosis; nonalcoholic steatohepatitis; platelet derived growth factor B; portal macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / metabolism*
  • Adult
  • Aged
  • Autocrine Communication*
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Kupffer Cells / enzymology*
  • Liver / enzymology*
  • Male
  • Middle Aged
  • Monocytes / enzymology*
  • Non-alcoholic Fatty Liver Disease / enzymology*
  • Paracrine Communication*
  • Proto-Oncogene Proteins c-sis / metabolism


  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins c-sis
  • ADA2 protein, human
  • Adenosine Deaminase