Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis

Life Sci Alliance. 2019 Dec 10;3(1):e201900465. doi: 10.26508/lsa.201900465. Print 2020 Jan.

Abstract

Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers / blood
  • Female
  • Follow-Up Studies
  • Humans
  • Immunity, Innate
  • Interleukin-6 / metabolism
  • Liver Cirrhosis / blood*
  • Liver Cirrhosis / mortality*
  • Lymphocyte Activation / genetics
  • Male
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Phagocytosis / genetics
  • Proto-Oncogene Proteins / blood*
  • Proto-Oncogene Proteins / genetics
  • Receptor Protein-Tyrosine Kinases / blood*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Severity of Illness Index*
  • Signal Transduction / genetics
  • THP-1 Cells
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Biomarkers
  • IL6 protein, human
  • Interleukin-6
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor-alpha
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase