Adenosine deaminase 2 produced by infiltrative monocytes promotes liver fibrosis in nonalcoholic fatty liver disease. Academic Article uri icon

Overview

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.

publication date

  • October 26, 2021

Research

keywords

  • Adenosine Deaminase
  • Autocrine Communication
  • Intercellular Signaling Peptides and Proteins
  • Kupffer Cells
  • Liver
  • Monocytes
  • Non-alcoholic Fatty Liver Disease
  • Paracrine Communication

Identity

PubMed Central ID

  • PMC8606247

Scopus Document Identifier

  • 85119106886

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0011049

PubMed ID

  • 34706243

Additional Document Info

volume

  • 37

issue

  • 4