Publikation
Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis
Wissenschaftlicher Artikel/Review - 10.12.2019
Brenig Robert, Antoniades Charalambos G, Wendon Julia, Heim Markus H, Ludewig Burkhard, Weston Christopher J, Duong François Ht, Semela David, Brand Stephan, Boldanova Tuyana, Künzler-Heule Patrizia, Cupovic Jovana, Besse Lenka, Pérez Shibayama Christian Ivan, Singanayagam Arjuna, Geng Anne, Triantafyllou Evangelos, Pop Oltin, Bernsmeier Christine
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Kurzbeschreibung/Zielsetzung
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 (CD14CD16HLA-DR) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of 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.