RT Journal Article
SR Electronic
T1 Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900465
DO 10.26508/lsa.201900465
VO 3
IS 1
A1 Robert Brenig
A1 Oltin T Pop
A1 Evangelos Triantafyllou
A1 Anne Geng
A1 Arjuna Singanayagam
A1 Christian Perez-Shibayama
A1 Lenka Besse
A1 Jovana Cupovic
A1 Patrizia Künzler
A1 Tuyana Boldanova
A1 Stephan Brand
A1 David Semela
A1 François HT Duong
A1 Christopher J Weston
A1 Burkhard Ludewig
A1 Markus H Heim
A1 Julia Wendon
A1 Charalambos G Antoniades
A1 Christine Bernsmeier
YR 2020
UL https://www.life-science-alliance.org/content/3/1/e201900465.abstract
AB 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.