AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells

Oltin-Tiberiu Pop; Anne Geng; Emilio Flint; Arjuna Singanayagam; Caner Ercan; Lucia Possamai; Vishal C Patel; Patrizia Kuenzler; Marie-Anne Meier; Savas Soysal; Petr Hruz; Otto Kollmar; Kate C Tatham; Josie K Ward; Beat Müllhaupt; Achim Weber; Julia Wendon; Jan Hendrik Niess; Markus Heim; David Semela; Christopher Weston; Charalambos G Antoniades; Luigi Maria Terracciano; Evangelos Triantafyllou; Robert G Brenig; Christine Bernsmeier

doi:10.1016/j.jcmgh.2023.03.007

AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells

Oltin-Tiberiu Pop, Anne Geng, Emilio Flint, Arjuna Singanayagam, Caner Ercan, Lucia Possamai, Vishal C Patel, Patrizia Kuenzler, Marie-Anne Meier, Savas Soysal, Petr Hruz, Otto Kollmar, Kate C Tatham, Josie K Ward, Beat Müllhaupt, Achim Weber, Julia Wendon, Jan Hendrik Niess, Markus Heim, David SemelaChristopher Weston, Charalambos G Antoniades, Luigi Maria Terracciano, Evangelos Triantafyllou, Robert G Brenig^*, Christine Bernsmeier^*

^*Corresponding author for this work

Immunology and Immunotherapy

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

Abstract

BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14 +HLA-DR +AXL +) and acute-on-chronic liver failure (CD14 +MERTK +). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced TNF-α/IL-6 production and T cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment- but not interstitial lung-, and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis.

METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n=22), chronic liver disease (n=8), non-cirrhotic portal hypertension (n=4) and healthy controls (n=4). Phenotype and function of isolated primary human liver macrophages were characterised by flow cytometry (cirrhosis, n=11; control, n=14) ex vivo. Also, AXL expression was assessed on peritoneal- (n=29) and gut macrophages (n=16) from cirrhotic patients. Regulation of AXL expression was analysed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells and GAS6 in co-culture experiments.

RESULTS: AXL was expressed on resident (CD68 +) but not tissue-infiltrating (MAC387 +) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68 +AXL + cells significantly decreased with cirrhosis progression: (Healthy 90.2%; Child Pugh A 76.1%; B 64.5%; C 18.7%, all p<0.05) and negatively correlated with MELD and CRP (all p<0.05). AXL-expressing hepatic macrophages were CD68 highHLA-DR highCD16 highCD206 high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients, but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro.

CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSCs-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

Original language	English
Journal	Cellular and molecular gastroenterology and hepatology
Early online date	31 Mar 2023
DOIs	https://doi.org/10.1016/j.jcmgh.2023.03.007
Publication status	E-pub ahead of print - 31 Mar 2023

Bibliographical note

Keywords

TAM receptors
innate immunity
cirrhosis
resident liver macrophages

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Pop, O.-T., Geng, A., Flint, E., Singanayagam, A., Ercan, C., Possamai, L., Patel, V. C., Kuenzler, P., Meier, M.-A., Soysal, S., Hruz, P., Kollmar, O., Tatham, K. C., Ward, J. K., Müllhaupt, B., Weber, A., Wendon, J., Niess, J. H., Heim, M., ... Bernsmeier, C. (2023). AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells. Cellular and molecular gastroenterology and hepatology. Advance online publication. https://doi.org/10.1016/j.jcmgh.2023.03.007

@article{8bcf90cdcb3d47ffa8f197bc4dfcb375,

title = "AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells",

abstract = "BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14 +HLA-DR +AXL +) and acute-on-chronic liver failure (CD14 +MERTK +). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced TNF-α/IL-6 production and T cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment- but not interstitial lung-, and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n=22), chronic liver disease (n=8), non-cirrhotic portal hypertension (n=4) and healthy controls (n=4). Phenotype and function of isolated primary human liver macrophages were characterised by flow cytometry (cirrhosis, n=11; control, n=14) ex vivo. Also, AXL expression was assessed on peritoneal- (n=29) and gut macrophages (n=16) from cirrhotic patients. Regulation of AXL expression was analysed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells and GAS6 in co-culture experiments.RESULTS: AXL was expressed on resident (CD68 +) but not tissue-infiltrating (MAC387 +) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68 +AXL + cells significantly decreased with cirrhosis progression: (Healthy 90.2%; Child Pugh A 76.1%; B 64.5%; C 18.7%, all p<0.05) and negatively correlated with MELD and CRP (all p<0.05). AXL-expressing hepatic macrophages were CD68 highHLA-DR highCD16 highCD206 high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients, but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSCs-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.",

keywords = "TAM receptors, innate immunity, cirrhosis, resident liver macrophages",

author = "Oltin-Tiberiu Pop and Anne Geng and Emilio Flint and Arjuna Singanayagam and Caner Ercan and Lucia Possamai and Patel, {Vishal C} and Patrizia Kuenzler and Marie-Anne Meier and Savas Soysal and Petr Hruz and Otto Kollmar and Tatham, {Kate C} and Ward, {Josie K} and Beat M{\"u}llhaupt and Achim Weber and Julia Wendon and Niess, {Jan Hendrik} and Markus Heim and David Semela and Christopher Weston and Antoniades, {Charalambos G} and Terracciano, {Luigi Maria} and Evangelos Triantafyllou and Brenig, {Robert G} and Christine Bernsmeier",

note = "Copyright {\textcopyright} 2023 The Authors. Published by Elsevier Inc.",

year = "2023",

month = mar,

day = "31",

doi = "10.1016/j.jcmgh.2023.03.007",

language = "English",

journal = "Cellular and molecular gastroenterology and hepatology",

issn = "2352-345X",

publisher = "Elsevier",

}

Pop, O-T, Geng, A, Flint, E, Singanayagam, A, Ercan, C, Possamai, L, Patel, VC, Kuenzler, P, Meier, M-A, Soysal, S, Hruz, P, Kollmar, O, Tatham, KC, Ward, JK, Müllhaupt, B, Weber, A, Wendon, J, Niess, JH, Heim, M, Semela, D, Weston, C, Antoniades, CG, Terracciano, LM, Triantafyllou, E, Brenig, RG & Bernsmeier, C 2023, 'AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells', Cellular and molecular gastroenterology and hepatology. https://doi.org/10.1016/j.jcmgh.2023.03.007

TY - JOUR

T1 - AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells

AU - Pop, Oltin-Tiberiu

AU - Geng, Anne

AU - Flint, Emilio

AU - Singanayagam, Arjuna

AU - Ercan, Caner

AU - Possamai, Lucia

AU - Patel, Vishal C

AU - Kuenzler, Patrizia

AU - Meier, Marie-Anne

AU - Soysal, Savas

AU - Hruz, Petr

AU - Kollmar, Otto

AU - Tatham, Kate C

AU - Ward, Josie K

AU - Müllhaupt, Beat

AU - Weber, Achim

AU - Wendon, Julia

AU - Niess, Jan Hendrik

AU - Heim, Markus

AU - Semela, David

AU - Weston, Christopher

AU - Antoniades, Charalambos G

AU - Terracciano, Luigi Maria

AU - Triantafyllou, Evangelos

AU - Brenig, Robert G

AU - Bernsmeier, Christine

PY - 2023/3/31

Y1 - 2023/3/31

N2 - BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14 +HLA-DR +AXL +) and acute-on-chronic liver failure (CD14 +MERTK +). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced TNF-α/IL-6 production and T cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment- but not interstitial lung-, and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n=22), chronic liver disease (n=8), non-cirrhotic portal hypertension (n=4) and healthy controls (n=4). Phenotype and function of isolated primary human liver macrophages were characterised by flow cytometry (cirrhosis, n=11; control, n=14) ex vivo. Also, AXL expression was assessed on peritoneal- (n=29) and gut macrophages (n=16) from cirrhotic patients. Regulation of AXL expression was analysed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells and GAS6 in co-culture experiments.RESULTS: AXL was expressed on resident (CD68 +) but not tissue-infiltrating (MAC387 +) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68 +AXL + cells significantly decreased with cirrhosis progression: (Healthy 90.2%; Child Pugh A 76.1%; B 64.5%; C 18.7%, all p<0.05) and negatively correlated with MELD and CRP (all p<0.05). AXL-expressing hepatic macrophages were CD68 highHLA-DR highCD16 highCD206 high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients, but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSCs-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

AB - BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14 +HLA-DR +AXL +) and acute-on-chronic liver failure (CD14 +MERTK +). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced TNF-α/IL-6 production and T cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment- but not interstitial lung-, and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n=22), chronic liver disease (n=8), non-cirrhotic portal hypertension (n=4) and healthy controls (n=4). Phenotype and function of isolated primary human liver macrophages were characterised by flow cytometry (cirrhosis, n=11; control, n=14) ex vivo. Also, AXL expression was assessed on peritoneal- (n=29) and gut macrophages (n=16) from cirrhotic patients. Regulation of AXL expression was analysed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells and GAS6 in co-culture experiments.RESULTS: AXL was expressed on resident (CD68 +) but not tissue-infiltrating (MAC387 +) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68 +AXL + cells significantly decreased with cirrhosis progression: (Healthy 90.2%; Child Pugh A 76.1%; B 64.5%; C 18.7%, all p<0.05) and negatively correlated with MELD and CRP (all p<0.05). AXL-expressing hepatic macrophages were CD68 highHLA-DR highCD16 highCD206 high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients, but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSCs-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

KW - TAM receptors

KW - innate immunity

KW - cirrhosis

KW - resident liver macrophages

U2 - 10.1016/j.jcmgh.2023.03.007

DO - 10.1016/j.jcmgh.2023.03.007

M3 - Article

C2 - 37004869

SN - 2352-345X

JO - Cellular and molecular gastroenterology and hepatology

JF - Cellular and molecular gastroenterology and hepatology

ER -

AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells

Abstract

Bibliographical note

Keywords

UN SDGs

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