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

Robert Brenig; Oltin T. Pop; Evangelos Triantafyllou; Anne Geng; Arjuna Singanayagam; Christian Perez-Shibayama; Lenka Besse; Jovana Cupovic; Patrizia Künzler; Tuyana Boldanova; Stephan Brand; David Semela; François Ht Duong; Christopher J. Weston; Burkhard Ludewig; Markus H. Heim; Julia Wendon; Charalambos G. Antoniades; Christine Bernsmeier

doi:10.26508/lsa.201900465

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

Robert Brenig, Oltin T. Pop, Evangelos Triantafyllou, Anne Geng, Arjuna Singanayagam, Christian Perez-Shibayama, Lenka Besse, Jovana Cupovic, Patrizia Künzler, Tuyana Boldanova, Stephan Brand, David Semela, François Ht Duong, Christopher J. Weston, Burkhard Ludewig, Markus H. Heim, Julia Wendon, Charalambos G. Antoniades, Christine Bernsmeier

Inflammation Biology

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

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.

Original language	English
Article number	e201900465
Journal	Life Science Alliance
Volume	3
Issue number	1
DOIs	https://doi.org/10.26508/lsa.201900465
Publication status	Published - 1 Jan 2020

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Brenig, R., Pop, O. T., Triantafyllou, E., Geng, A., Singanayagam, A., Perez-Shibayama, C., Besse, L., Cupovic, J., Künzler, P., Boldanova, T., Brand, S., Semela, D., Duong, F. H., Weston, C. J., Ludewig, B., Heim, M. H., Wendon, J., Antoniades, C. G., & Bernsmeier, C. (2020). Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis. Life Science Alliance, 3(1), Article e201900465. https://doi.org/10.26508/lsa.201900465

@article{b3b6c82e7f6e4efa9a40994651e47d5e,

title = "Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis",

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.",

author = "Robert Brenig and Pop, {Oltin T.} and Evangelos Triantafyllou and Anne Geng and Arjuna Singanayagam and Christian Perez-Shibayama and Lenka Besse and Jovana Cupovic and Patrizia K{\"u}nzler and Tuyana Boldanova and Stephan Brand and David Semela and Duong, {Fran{\c c}ois Ht} and Weston, {Christopher J.} and Burkhard Ludewig and Heim, {Markus H.} and Julia Wendon and Antoniades, {Charalambos G.} and Christine Bernsmeier",

year = "2020",

month = jan,

day = "1",

doi = "10.26508/lsa.201900465",

language = "English",

volume = "3",

journal = "Life Science Alliance",

issn = "2575-1077",

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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, FH, 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, vol. 3, no. 1, e201900465. https://doi.org/10.26508/lsa.201900465

TY - JOUR

T1 - Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis

AU - Brenig, Robert

AU - Pop, Oltin T.

AU - Triantafyllou, Evangelos

AU - Geng, Anne

AU - Singanayagam, Arjuna

AU - Perez-Shibayama, Christian

AU - Besse, Lenka

AU - Cupovic, Jovana

AU - Künzler, Patrizia

AU - Boldanova, Tuyana

AU - Brand, Stephan

AU - Semela, David

AU - Duong, François Ht

AU - Weston, Christopher J.

AU - Ludewig, Burkhard

AU - Heim, Markus H.

AU - Wendon, Julia

AU - Antoniades, Charalambos G.

AU - Bernsmeier, Christine

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85076360830&partnerID=8YFLogxK

U2 - 10.26508/lsa.201900465

DO - 10.26508/lsa.201900465

M3 - Article

C2 - 31822557

AN - SCOPUS:85076360830

SN - 2575-1077

VL - 3

JO - Life Science Alliance

JF - Life Science Alliance

IS - 1

M1 - e201900465

ER -

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

Abstract

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