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

Brenig, R; Pop, OT; Triantafyllou, E; Geng, A; Singanayagam, A; Perez-Shibayama, C; Besse, L; Cupovic, J; Künzler, P; Boldanova, T; et al. Brenig, R; Pop, OT; Triantafyllou, E; Geng, A; Singanayagam, A; Perez-Shibayama, C; Besse, L; Cupovic, J; Künzler, P; Boldanova, T; Brand, S; Semela, D; Duong, FHT; Weston, CJ; Ludewig, B; Heim, MH; Wendon, J; Antoniades, CG; Bernsmeier, C (2020) Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis. Life Science Alliance, 3 (1). e201900465-e201900465. ISSN 2575-1077 https://doi.org/10.26508/lsa.201900465
SGUL Authors: Singanayagam, Arjuna

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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.

Item Type: Article
Additional Information: © 2019 Brenig et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Life Science Alliance
ISSN: 2575-1077
Language: en
Dates:
DateEvent
January 2020Published
10 December 2019Published Online
2 December 2019Accepted
Projects:
Project IDFunderFunder ID
320030_159984Swiss National Science Foundationhttp://dx.doi.org/10.13039/501100001711
14/17Cantonal Hospital St. GallenUNSPECIFIED
URI: http://openaccess.sgul.ac.uk/id/eprint/111489
Publisher's version: https://doi.org/10.26508/lsa.201900465

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