Download PDF
CC BY-NC-ND 4.0 · Semin Liver Dis 2024; 44(01): 099-114
DOI: 10.1055/a-2275-0408
Review Article

GAS6/TAM Axis as Therapeutic Target in Liver Diseases

Anna Tutusaus
1   Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalunya, Spain
3   Barcelona Clinic Liver Cancer (BCLC) Group, Barcelona, Spain
,
Albert Morales
1   Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalunya, Spain
3   Barcelona Clinic Liver Cancer (BCLC) Group, Barcelona, Spain
,
Pablo García de Frutos
1   Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalunya, Spain
2   Centro de Investigación Biomédica en Red sobre Enfermedades Cardiovasculares (CIBERCV), Barcelona, Comunidad de Madrid, Spain
,
Montserrat Marí
1   Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Catalunya, Spain
3   Barcelona Clinic Liver Cancer (BCLC) Group, Barcelona, Spain
› Author Affiliations Funding This research was funded by Instituto de Salud Carlos III (Project# PI22/00475 to M.M.) and by Ministerio de Ciencia e Innovación (PID2021-123564OB-I00, MCIN/AEI/10.13039/501100011033 to A.M. and P.G.F.), and co-funded by the European Union “ERDF A Way of Making Europe” (Next Generation EU/PRTR); CIBERCV; AGAUR (2021_SGR_490) and CERCA Programme/Generalitat de Catalunya; and Fundació la Marató de TV3 (202133-32) to A.M. and P.G.F. This research also received research funding and Sponsored Research Agreement, from BerGenBio ASA.
› Further Information
   Permissions and Reprints


Abstract

TAM (TYRO3, AXL, and MERTK) protein tyrosine kinase membrane receptors and their vitamin K-dependent ligands GAS6 and protein S (PROS) are well-known players in tumor biology and autoimmune diseases. In contrast, TAM regulation of fibrogenesis and the inflammation mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and, ultimately, liver cancer has recently been revealed. GAS6 and PROS binding to phosphatidylserine exposed in outer membranes of apoptotic cells links TAMs, particularly MERTK, with hepatocellular damage. In addition, AXL and MERTK regulate the development of liver fibrosis and inflammation in chronic liver diseases. Acute hepatic injury is also mediated by the TAM system, as recent data regarding acetaminophen toxicity and acute-on-chronic liver failure have uncovered. Soluble TAM-related proteins, mainly released from activated macrophages and hepatic stellate cells after hepatic deterioration, are proposed as early serum markers for disease progression. In conclusion, the TAM system is becoming an interesting pharmacological target in liver pathology and a focus of future biomedical research in this field.

Keywords

phagocytosis - fibrosis - inflammation - cytokine regulation - biomarkers


Publication History

Accepted Manuscript online:
23 February 2024

Article published online:
21 March 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 van der Meer JHM, van der Poll T, van 't Veer C. TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis. Blood 2014; 123 (16) 2460-2469
    CrossrefPubMedGoogle Scholar
  • 2 Lai C, Lemke G. An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron 1991; 6 (05) 691-704
    CrossrefPubMedGoogle Scholar
  • 3 Ohashi K, Nagata K, Toshima J. et al. Stimulation of sky receptor tyrosine kinase by the product of growth arrest-specific gene 6. J Biol Chem 1995; 270 (39) 22681-22684
    CrossrefPubMedGoogle Scholar
  • 4 Stitt TN, Conn G, Gore M. et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 1995; 80 (04) 661-670
    CrossrefPubMedGoogle Scholar
  • 5 Tsou WI, Nguyen KQN, Calarese DA. et al. Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. J Biol Chem 2014; 289 (37) 25750-25763
    CrossrefPubMedGoogle Scholar
  • 6 Lew ED, Oh J, Burrola PG. et al. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife 2014; 3: e03385
    CrossrefPubMedGoogle Scholar
  • 7 Geng K, Kumar S, Kimani SG. et al. Requirement of gamma-carboxyglutamic acid modification and phosphatidylserine binding for the activation of Tyro3, Axl, and Mertk receptors by growth arrest-specific 6. Front Immunol 2017; 8 (November): 1521
    CrossrefPubMedGoogle Scholar
  • 8 Sadahiro H, Kang KD, Gibson JT. et al. Activation of the receptor tyrosine kinase AXL regulates the immune microenvironment in glioblastoma. Cancer Res 2018; 78 (11) 3002-3013
    CrossrefPubMedGoogle Scholar
  • 9 Wu Q, Li X, Yang Y. et al. MICA+ tumor cell upregulated macrophage-secreted MMP9 via PROS1-AXL axis to induce tumor immune escape in advanced hepatocellular carcinoma (HCC). Cancers (Basel) 2024; 16 (02) 269
    CrossrefPubMedGoogle Scholar
  • 10 Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol 2007; 178 (09) 5635-5642
    CrossrefPubMedGoogle Scholar
  • 11 Pierce A, Bliesner B, Xu M. et al. Axl and Tyro3 modulate female reproduction by influencing gonadotropin-releasing hormone neuron survival and migration. Mol Endocrinol 2008; 22 (11) 2481-2495
    CrossrefPubMedGoogle Scholar
  • 12 Rothlin CV, Ghosh S, Zuniga EI, Oldstone MBA, Lemke G. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 2007; 131 (06) 1124-1136
    CrossrefPubMedGoogle Scholar
  • 13 Ruan GX, Kazlauskas A. Axl is essential for VEGF-A-dependent activation of PI3K/Akt. EMBO J 2012; 31 (07) 1692-1703
    CrossrefPubMedGoogle Scholar
  • 14 Vouri M, Croucher DR, Kennedy SP, An Q, Pilkington GJ, Hafizi S. Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells. Oncogenesis 2016; 5 (10) e266
    CrossrefPubMedGoogle Scholar
  • 15 Sather S, Kenyon KD, Lefkowitz JB. et al. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood 2007; 109 (03) 1026-1033
    CrossrefPubMedGoogle Scholar
  • 16 O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET. The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage. J Biol Chem 1995; 270 (02) 551-557
    CrossrefPubMedGoogle Scholar
  • 17 Lu Q, Gore M, Zhang Q. et al. Tyro-3 family receptors are essential regulators of mammalian spermatogenesis. Nature 1999; 398 (6729): 723-728
    CrossrefPubMedGoogle Scholar
  • 18 Lu Q, Lemke G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro 3 family. Science 2001; 293 (5528): 306-311
    CrossrefPubMedGoogle Scholar
  • 19 Camenisch TD, Koller BH, Earp HS, Matsushima GK. A novel receptor tyrosine kinase, Mer, inhibits TNF-alpha production and lipopolysaccharide-induced endotoxic shock. J Immunol 1999; 162 (06) 3498-3503
    CrossrefPubMedGoogle Scholar
  • 20 Sharif MN, Sosic D, Rothlin CV. et al. Twist mediates suppression of inflammation by type I IFNs and Axl. J Exp Med 2006; 203 (08) 1891-1901
    CrossrefPubMedGoogle Scholar
  • 21 Paolino M, Choidas A, Wallner S. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014; 507 (7493): 508-512
    CrossrefPubMedGoogle Scholar
  • 22 Chirino LM, Kumar S, Okumura M. et al. TAM receptors attenuate murine NK-cell responses via E3 ubiquitin ligase Cbl-b. Eur J Immunol 2020; 50 (01) 48-55
    CrossrefPubMedGoogle Scholar
  • 23 Mahajan NP, Earp HS. An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action. J Biol Chem 2003; 278 (43) 42596-42603
    CrossrefPubMedGoogle Scholar
  • 24 Lemke G, Burstyn-Cohen T. TAM receptors and the clearance of apoptotic cells. Ann N Y Acad Sci 2010; 1209 (01) 23-29
    CrossrefPubMedGoogle Scholar
  • 25 Wu Y, Singh S, Georgescu MM, Birge RB. A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci 2005; 118 (Pt 3): 539-553
    CrossrefPubMedGoogle Scholar
  • 26 Wang H, Chen Y, Ge Y. et al. Immunoexpression of Tyro 3 family receptors–Tyro 3, Axl, and Mer–and their ligand Gas6 in postnatal developing mouse testis. J Histochem Cytochem 2005; 53 (11) 1355-1364
    CrossrefPubMedGoogle Scholar
  • 27 Nakanishi Y, Shiratsuchi A. Phagocytic removal of apoptotic spermatogenic cells by Sertoli cells: mechanisms and consequences. Biol Pharm Bull 2004; 27 (01) 13-16
    CrossrefPubMedGoogle Scholar
  • 28 Prasad D, Rothlin CV, Burrola P. et al. TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci 2006; 33 (01) 96-108
    CrossrefPubMedGoogle Scholar
  • 29 Burstyn-Cohen T, Lew ED, Través PG, Burrola PG, Hash JC, Lemke G. Genetic dissection of TAM receptor-ligand interaction in retinal pigment epithelial cell phagocytosis. Neuron 2012; 76 (06) 1123-1132
    CrossrefPubMedGoogle Scholar
  • 30 Scott RS, McMahon EJ, Pop SM. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 2001; 411 (6834): 207-211
    CrossrefPubMedGoogle Scholar
  • 31 Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature 1997; 390 (6658): 350-351
    CrossrefPubMedGoogle Scholar
  • 32 Sen P, Wallet MA, Yi Z. et al. Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells. Blood 2007; 109 (02) 653-660
    CrossrefPubMedGoogle Scholar
  • 33 Eken C, Martin PJ, Sadallah S, Treves S, Schaller M, Schifferli JA. Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages. J Biol Chem 2010; 285 (51) 39914-39921
    CrossrefPubMedGoogle Scholar
  • 34 Adomati T, Cham LB, Hamdan TA. et al. Dead cells induce innate anergy via MerTK after acute viral infection. Cell Rep 2020; 30 (11) 3671-3681.e5
    CrossrefPubMedGoogle Scholar
  • 35 Park HJ, Baen JY, Lee YJ, Choi YH, Kang JL. The TAM-family receptor Mer mediates production of HGF through the RhoA-dependent pathway in response to apoptotic cells. Mol Biol Cell 2012; 23 (16) 3254-3265
    CrossrefPubMedGoogle Scholar
  • 36 Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol 2008; 8 (05) 327-336
    CrossrefPubMedGoogle Scholar
  • 37 Wallet MA, Sen P, Flores RR. et al. MerTK is required for apoptotic cell-induced T cell tolerance. J Exp Med 2008; 205 (01) 219-232
    CrossrefPubMedGoogle Scholar
  • 38 Zagórska A, Través PG, Lew ED, Dransfield I, Lemke G. Diversification of TAM receptor tyrosine kinase function. Nat Immunol 2014; 15 (10) 920-928
    CrossrefPubMedGoogle Scholar
  • 39 Huang Y, Happonen KE, Burrola PG. et al. Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat Immunol 2021; 22 (05) 586-594
    CrossrefPubMedGoogle Scholar
  • 40 Wang ZY, Wang PG, An J. The multifaceted roles of TAM receptors during viral infection. Virol Sin 2021; 36 (01) 1-12
    CrossrefPubMedGoogle Scholar
  • 41 Amara A, Mercer J. Viral apoptotic mimicry. Nat Rev Microbiol 2015; 13 (08) 461-469
    CrossrefPubMedGoogle Scholar
  • 42 Shimojima M, Takada A, Ebihara H. et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol 2006; 80 (20) 10109-10116
    CrossrefPubMedGoogle Scholar
  • 43 Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 2016; 18 (05) 591-596
    CrossrefPubMedGoogle Scholar
  • 44 Meertens L, Carnec X, Lecoin MP. et al. The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe 2012; 12 (04) 544-557
    CrossrefPubMedGoogle Scholar
  • 45 Bouhaddou M, Memon D, Meyer B. et al. The global phosphorylation landscape of SARS-CoV-2 infection. Cell 2020; 182 (03) 685-712.e19
    CrossrefPubMedGoogle Scholar
  • 46 Tutusaus A, Marí M, Ortiz-Pérez JT, Nicolaes GAF, Morales A, García de Frutos P. Role of vitamin K-dependent factors protein S and GAS6 and TAM receptors in SARS-CoV-2 infection and COVID-19-associated immunothrombosis. Cells 2020; 9 (10) 2186
    CrossrefPubMedGoogle Scholar
  • 47 Bohan D, Van Ert H, Ruggio N. et al. Phosphatidylserine receptors enhance SARS-CoV-2 infection. PLoS Pathog 2021; 17 (11) e1009743
    CrossrefPubMedGoogle Scholar
  • 48 Nautiyal J, Madeleine N, Bohan D. et al. Bemcentinib modulation of inflammatory, fibrotic and tissue repair pathways corresponds with favourable clinical outcomes in hospitalised COVID-19 patients demonstrating higher severity cues: a biomarker perspective. In: European Congress of Clinical Microbiology and Infectious Diseases; 2022
    PubMed
  • 49 Morales A, Rojo Rello S, Cristóbal H. et al. Growth arrest-specific factor 6 (GAS6) is increased in COVID-19 patients and predicts clinical outcome. Biomedicines 2021; 9 (04) 335
    CrossrefPubMedGoogle Scholar
  • 50 Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 2014; 14 (12) 769-785
    CrossrefPubMedGoogle Scholar
  • 51 Peeters MJW, Rahbech A, Thor Straten P. TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting. Cancer Immunol Immunother 2020; 69 (02) 237-244
    CrossrefPubMedGoogle Scholar
  • 52 Burstyn-Cohen T, Maimon A. TAM receptors, phosphatidylserine, inflammation, and cancer. Cell Commun Signal 2019; 17 (01) 156
    CrossrefPubMedGoogle Scholar
  • 53 Paolino M, Penninger JM. The role of TAM family receptors in immune cell function: implications for cancer therapy. Cancers (Basel) 2016; 8 (10) 97
    CrossrefPubMedGoogle Scholar
  • 54 Goruppi S, Ruaro E, Varnum B, Schneider C. Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras. Oncogene 1999; 18 (29) 4224-4236
    CrossrefPubMedGoogle Scholar
  • 55 Schlegel J, Sambade MJ, Sather S. et al. MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J Clin Invest 2013; 123 (05) 2257-2267
    CrossrefPubMedGoogle Scholar
  • 56 Guttridge KL, Luft JC, Dawson TL. et al. Mer receptor tyrosine kinase signaling: prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation. J Biol Chem 2002; 277 (27) 24057-24066
    CrossrefPubMedGoogle Scholar
  • 57 Holland SJ, Powell MJ, Franci C. et al. Multiple roles for the receptor tyrosine kinase axl in tumor formation. Cancer Res 2005; 65 (20) 9294-9303
    CrossrefPubMedGoogle Scholar
  • 58 Ruan GX, Kazlauskas A. Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. J Biol Chem 2013; 288 (29) 21161-21172
    CrossrefPubMedGoogle Scholar
  • 59 Tanaka M, Siemann DW. Axl signaling is an important mediator of tumor angiogenesis. Oncotarget 2019; 10 (30) 2887-2898
    CrossrefPubMedGoogle Scholar
  • 60 Li Y, Ye X, Tan C. et al. Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis. Oncogene 2009; 28 (39) 3442-3455
    CrossrefPubMedGoogle Scholar
  • 61 Tanaka M, Siemann DW. Gas6/Axl signaling pathway in the tumor immune microenvironment. Cancers (Basel) 2020; 12 (07) 1850
    CrossrefPubMedGoogle Scholar
  • 62 Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev 2017; 276 (01) 165-177
    CrossrefPubMedGoogle Scholar
  • 63 Yokoyama Y, Lew ED, Seelige R. et al. Immuno-oncological efficacy of RXDX-106, a Novel TAM (TYRO3, AXL, MER) family small-molecule kinase inhibitor. Cancer Res 2019; 79 (08) 1996-2008
    CrossrefPubMedGoogle Scholar
  • 64 Pop OT, Geng A, Flint E. et al. AXL expression on homeostatic resident liver macrophages is reduced in cirrhosis following GAS6 production by hepatic stellate cells. Cell Mol Gastroenterol Hepatol 2023; 16 (01) 17-37
    CrossrefPubMedGoogle Scholar
  • 65 Zagórska A, Través PG, Jiménez-García L. et al. Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer. Life Sci Alliance 2020; 3 (08) 1-15
    CrossrefPubMedGoogle Scholar
  • 66 Lafdil F, Chobert MN, Couchie D. et al. Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells. Hepatology 2006; 44 (01) 228-239
    CrossrefPubMedGoogle Scholar
  • 67 MacParland SA, Liu JC, Ma X-Z. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat Commun 2018; 9 (1): 4383
    CrossrefPubMedGoogle Scholar
  • 68 Qi N, Liu P, Zhang Y, Wu H, Chen Y, Han D. Development of a spontaneous liver disease resembling autoimmune hepatitis in mice lacking tyro3, Axl and Mer receptor tyrosine kinases. PLoS One 2013; 8 (06) e66604
    CrossrefPubMedGoogle Scholar
  • 69 Ferrero M, Desiderio MA, Martinotti A. et al. Expression of a growth arrest specific gene (gas-6) during liver regeneration: molecular mechanisms and signalling pathways. J Cell Physiol 1994; 158 (02) 263-269
    CrossrefPubMedGoogle Scholar
  • 70 Couchie D, Lafdil F, Martin-Garcia N, Laperche Y, Zafrani ES, Mavier P. Expression and role of Gas6 protein and of its receptor Axl in hepatic regeneration from oval cells in the rat. Gastroenterology 2005; 129 (05) 1633-1642
    CrossrefPubMedGoogle Scholar
  • 71 Ortmayr G, Brunnthaler L, Pereyra D. et al. Immunological aspects of AXL/GAS-6 in the context of human liver regeneration. Hepatol Commun 2022; 6 (03) 576-592
    CrossrefPubMedGoogle Scholar
  • 72 Santamaria-Barria JA, Zeng S, Greer JB. et al. Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells. PLoS One 2019; 14 (05) e0216275
    CrossrefPubMedGoogle Scholar
  • 73 Lafdil F, Chobert MN, Deveaux V. et al. Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice. J Hepatol 2009; 51 (01) 55-66
    CrossrefPubMedGoogle Scholar
  • 74 Tjwa M, Bellido-Martin L, Lin Y. et al. Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes. Blood 2008; 111 (08) 4096-4105
    CrossrefPubMedGoogle Scholar
  • 75 Llacuna L, Bárcena C, Bellido-Martín L. et al. Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury. Hepatology 2010; 52 (04) 1371-1379
    CrossrefPubMedGoogle Scholar
  • 76 Wang Z, Liu D, Yan Q. et al. Activated AXL protects against hepatic ischemia-reperfusion injury by upregulating SOCS-1 expression. Transplantation 2022; 106 (07) 1351-1364
    CrossrefPubMedGoogle Scholar
  • 77 Harris J, Lang T, Thomas JPW, Sukkar MB, Nabar NR, Kehrl JH. Autophagy and inflammasomes. Mol Immunol 2017; 86: 10-15
    CrossrefPubMedGoogle Scholar
  • 78 Green DR, Oguin TH, Martinez J. The clearance of dying cells: table for two. Cell Death Differ 2016; 23 (06) 915-926
    CrossrefPubMedGoogle Scholar
  • 79 Galimberti VE, Rothlin CV, Ghosh S. Funerals and feasts: the immunological rites of cell death. Yale J Biol Med 2019; 92 (04) 663-674
    PubMedGoogle Scholar
  • 80 Han J, Bae J, Choi CY. et al. Autophagy induced by AXL receptor tyrosine kinase alleviates acute liver injury via inhibition of NLRP3 inflammasome activation in mice. Autophagy 2016; 12 (12) 2326-2343
    CrossrefPubMedGoogle Scholar
  • 81 Triantafyllou E, Pop OT, Possamai LA. et al. MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure. Gut 2018; 67 (02) 333-347
    CrossrefPubMedGoogle Scholar
  • 82 Kopec AK, Joshi N, Cline-Fedewa H. et al. Fibrin(ogen) drives repair after acetaminophen-induced liver injury via leukocyte αMβ2 integrin-dependent upregulation of Mmp12. J Hepatol 2017; 66 (04) 787-797
    CrossrefPubMedGoogle Scholar
  • 83 Xiao Y, Zhao H, Tian L. et al. S100A10 is a critical mediator of GAS6/AXL-induced angiogenesis in renal cell carcinoma. Cancer Res 2019; 79 (22) 5758-5768
    CrossrefPubMedGoogle Scholar
  • 84 Horst AK, Tiegs G, Diehl L. Contribution of macrophage efferocytosis to liver homeostasis and disease. Front Immunol 2019; 10: 2670
    CrossrefPubMedGoogle Scholar
  • 85 Read SA, Tay ES, Shahidi M, McLauchlan J, George J, Douglas MW. The mechanism of interferon refractoriness during hepatitis C virus infection and its reversal with a peroxisome proliferator-activated receptor α agonist. J Interferon Cytokine Res 2015; 35 (06) 488-497
    CrossrefPubMedGoogle Scholar
  • 86 Read SA, Tay ES, Shahidi M. et al. Hepatitis C virus driven AXL expression suppresses the hepatic Type I interferon response. PLoS One 2015; 10 (08) e0136227
    CrossrefPubMedGoogle Scholar
  • 87 Patin E, Kutalik Z, Guergnon J. et al; Swiss Hepatitis C Cohort Study Group, International Hepatitis C Genetics Consortium, French ANRS HC EP 26 Genoscan Study Group. Genome-wide association study identifies variants associated with progression of liver fibrosis from HCV infection. Gastroenterology 2012; 143 (05) 1244-1252.e12
    CrossrefPubMedGoogle Scholar
  • 88 Rüeger S, Bochud PY, Dufour JF. et al. Impact of common risk factors of fibrosis progression in chronic hepatitis C. Gut 2015; 64 (10) 1605-1615
    CrossrefPubMedGoogle Scholar
  • 89 Jiménez-Sousa MÁ, Gómez-Moreno AZ, Pineda-Tenor D. et al. The myeloid-epithelial-reproductive tyrosine kinase (MERTK) rs4374383 polymorphism predicts progression of liver fibrosis in hepatitis C virus-infected patients: a longitudinal study. J Clin Med 2018; 7 (12) 473
    CrossrefPubMedGoogle Scholar
  • 90 Kupcinskas J, Valantiene I, Varkalaitė G. et al. PNPLA3 and RNF7 gene variants are associated with the risk of developing liver fibrosis and cirrhosis in an Eastern European population. J Gastrointestin Liver Dis 2017; 26 (01) 37-43
    CrossrefPubMedGoogle Scholar
  • 91 Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14 (07) 397-411
    CrossrefPubMedGoogle Scholar
  • 92 Totoki T, D' Alessandro-Gabazza CN, Toda M. et al. Protein S exacerbates chronic liver injury and fibrosis. Am J Pathol 2018; 188 (05) 1195-1203
    CrossrefPubMedGoogle Scholar
  • 93 Bárcena C, Stefanovic M, Tutusaus A. et al. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J Hepatol 2015; 63 (03) 670-678
    CrossrefPubMedGoogle Scholar
  • 94 Espindola MS, Habiel DM, Narayanan R. et al. Targeting of TAM receptors ameliorates fibrotic mechanisms in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2018; 197 (11) 1443-1456
    CrossrefPubMedGoogle Scholar
  • 95 Bellan M, Cittone MG, Tonello S. et al. Gas6/TAM system: a key modulator of the interplay between inflammation and fibrosis. Int J Mol Sci 2019; 20 (20) 5070
    CrossrefPubMedGoogle Scholar
  • 96 Bernsmeier C, van der Merwe S, Périanin A. Innate immune cells in cirrhosis. J Hepatol 2020; 73 (01) 186-201
    CrossrefPubMedGoogle Scholar
  • 97 Tsugawa H, Ohki T, Tsubaki S. et al. Gas6 ameliorates intestinal mucosal immunosenescence to prevent the translocation of a gut pathobiont, Klebsiella pneumoniae, to the liver. PLoS Pathog 2023; 19 (06) e1011139
    CrossrefPubMedGoogle Scholar
  • 98 Bernsmeier C, Pop OT, Singanayagam A. et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 2015; 148 (03) 603-615.e14
    CrossrefPubMedGoogle Scholar
  • 99 Brenig R, Pop OT, Triantafyllou E. et al. Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis. Life Sci Alliance 2019; 3 (01) e201900465
    CrossrefPubMedGoogle Scholar
  • 100 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
    CrossrefPubMedGoogle Scholar
  • 101 Cubero FJ. Staging NAFLD: diagnostic and therapeutic value of TAM signaling. Cell Mol Gastroenterol Hepatol 2020; 9 (03) 545-546
    CrossrefPubMedGoogle Scholar
  • 102 Wen Y, Ju C, Mer TK. A novel potential target to treat NASH fibrosis. Hepatology 2020; 72 (02) 772-774
    CrossrefPubMedGoogle Scholar
  • 103 Chiba T, Suzuki S, Sato Y, Itoh T, Umegaki K. Evaluation of methionine content in a high-fat and choline-deficient diet on body weight gain and the development of non-alcoholic steatohepatitis in mice. PLoS One 2016; 11 (10) e0164191
    CrossrefPubMedGoogle Scholar
  • 104 Tutusaus A, de Gregorio E, Cucarull B. et al. A functional role of GAS6/TAM in nonalcoholic steatohepatitis progression implicates AXL as therapeutic target. Cell Mol Gastroenterol Hepatol 2020; 9 (03) 349-368
    CrossrefPubMedGoogle Scholar
  • 105 DeBerge M, Glinton K, Subramanian M. et al. Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction. J Clin Invest 2021; 131 (06) e139576
    CrossrefPubMedGoogle Scholar
  • 106 Petta S, Valenti L, Marra F. et al. MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. J Hepatol 2016; 64 (03) 682-690
    CrossrefPubMedGoogle Scholar
  • 107 Musso G, Cassader M, De Michieli F. et al. MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat. Hum Mol Genet 2017; 26 (09) 1747-1758
    CrossrefPubMedGoogle Scholar
  • 108 Marí M, Tutusaus A, García de Frutos P, Morales A. Genetic and clinical data reinforce the role of GAS6 and TAM receptors in liver fibrosis. J Hepatol 2016; 64 (04) 983-984
    CrossrefPubMedGoogle Scholar
  • 109 Liu J, Yang C, Simpson C. et al. Discovery of novel small molecule Mer kinase inhibitors for the treatment of pediatric acute lymphoblastic leukemia. ACS Med Chem Lett 2012; 3 (02) 129-134
    CrossrefPubMedGoogle Scholar
  • 110 Pastore M, Caligiuri A, Raggi C. et al. Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators. JHEP Rep Innov Hepatol 2022; 4 (04) 100444
    CrossrefPubMedGoogle Scholar
  • 111 Cai X, Wang J, Wang J. et al. Intercellular crosstalk of hepatic stellate cells in liver fibrosis: new insights into therapy. Pharmacol Res 2020; 155: 104720
    CrossrefPubMedGoogle Scholar
  • 112 Cai B, Dongiovanni P, Corey KE. et al. Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis. Cell Metab 2020; 31 (02) 406-421.e7
    CrossrefPubMedGoogle Scholar
  • 113 Wang X, Zheng Z, Caviglia JM. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab 2016; 24 (06) 848-862
    CrossrefPubMedGoogle Scholar
  • 114 Ramachandran P, Pellicoro A, Vernon MA. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 2012; 109 (46) E3186-E3195
    CrossrefPubMedGoogle Scholar
  • 115 Duffield JS, Forbes SJ, Constandinou CM. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 2005; 115 (01) 56-65
    CrossrefPubMedGoogle Scholar
  • 116 Cai B, Thorp EB, Doran AC. et al. MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A 2016; 113 (23) 6526-6531
    CrossrefPubMedGoogle Scholar
  • 117 Cai B, Thorp EB, Doran AC. et al. MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 2017; 127 (02) 564-568
    CrossrefPubMedGoogle Scholar
  • 118 Junior, Lai YS, Nguyen HT, Salmanida FP, Chang KT. MERTK+/hi M2c macrophages induced by baicalin alleviate non-alcoholic fatty liver disease. Int J Mol Sci 2021; 22 (19) 10604
    CrossrefPubMedGoogle Scholar
  • 119 Gieseck III RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 2018; 18 (01) 62-76
    CrossrefPubMedGoogle Scholar
  • 120 Hart KM, Fabre T, Sciurba JC. et al. Type 2 immunity is protective in metabolic disease but exacerbates NAFLD collaboratively with TGF-β. Sci Transl Med 2017; 9 (396) eaal3694
    CrossrefPubMedGoogle Scholar
  • 121 Huang H, Jiang J, Chen R, Lin Y, Chen H, Ling Q. The role of macrophage TAM receptor family in the acute-to-chronic progression of liver disease: From friend to foe?. Liver Int 2022; 42 (12) 2620-2631
    CrossrefPubMedGoogle Scholar
  • 122 Chelakkot-Govindalayathil AL, Mifuji-Moroka R, D'Alessandro-Gabazza CN. et al. Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells. J Thromb Haemost 2015; 13 (01) 142-154
    CrossrefPubMedGoogle Scholar
  • 123 Cuño-Gómiz C, de Gregorio E, Tutusaus A. et al. Sex-based differences in natural killer T cell-mediated protection against diet-induced steatohepatitis in Balb/c mice. Biol Sex Differ 2023; 14 (01) 85
    CrossrefPubMedGoogle Scholar
  • 124 Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16 (10) 589-604
    CrossrefPubMedGoogle Scholar
  • 125 Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer 2019; 18 (01) 153
    CrossrefPubMedGoogle Scholar
  • 126 Hedrich V, Breitenecker K, Djerlek L, Ortmayr G, Mikulits W. Intrinsic and extrinsic control of hepatocellular carcinoma by TAM receptors. Cancers (Basel) 2021; 13 (21) 5448
    CrossrefPubMedGoogle Scholar
  • 127 Liu J, Wang K, Yan Z. et al. Axl expression stratifies patients with poor prognosis after hepatectomy for hepatocellular carcinoma. PLoS One 2016; 11 (05) e0154767
    CrossrefPubMedGoogle Scholar
  • 128 Pinato DJ, Brown MW, Trousil S. et al. Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma. Br J Cancer 2019; 120 (05) 512-521
    CrossrefPubMedGoogle Scholar
  • 129 Reichl P, Dengler M, van Zijl F. et al. Axl activates autocrine transforming growth factor-β signaling in hepatocellular carcinoma. Hepatology 2015; 61 (03) 930-941
    CrossrefPubMedGoogle Scholar
  • 130 Xu MZ, Chan SW, Liu AM. et al. AXL receptor kinase is a mediator of YAP-dependent oncogenic functions in hepatocellular carcinoma. Oncogene 2011; 30 (10) 1229-1240
    CrossrefPubMedGoogle Scholar
  • 131 Lee HJ, Jeng YM, Chen YL, Chung L, Yuan RH. Gas6/Axl pathway promotes tumor invasion through the transcriptional activation of Slug in hepatocellular carcinoma. Carcinogenesis 2014; 35 (04) 769-775
    CrossrefPubMedGoogle Scholar
  • 132 Haider C, Hnat J, Wagner R. et al. Transforming growth factor-β and Axl induce CXCL5 and neutrophil recruitment in hepatocellular carcinoma. Hepatology 2019; 69 (01) 222-236
    CrossrefPubMedGoogle Scholar
  • 133 Zhou SL, Zhou ZJ, Hu ZQ. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 2016; 150 (07) 1646-1658.e17
    CrossrefPubMedGoogle Scholar
  • 134 Shen L, Lei S, Zhang B. et al. Skipping of exon 10 in Axl pre-mRNA regulated by PTBP1 mediates invasion and metastasis process of liver cancer cells. Theranostics 2020; 10 (13) 5719-5735
    CrossrefPubMedGoogle Scholar
  • 135 Llovet JM, Ricci S, Mazzaferro V. et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359 (04) 378-390
    CrossrefPubMedGoogle Scholar
  • 136 Zhou L, Liu XD, Sun M. et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016; 35 (21) 2687-2697
    CrossrefPubMedGoogle Scholar
  • 137 Heffelfinger SC, Hawkins HH, Barrish J, Taylor L, Darlington GJSK. SK HEP-1: a human cell line of endothelial origin. In Vitro Cell Dev Biol 1992; 28A (02) 136-142
    CrossrefPubMedGoogle Scholar
  • 138 Scaltriti M, Elkabets M, Baselga J. Molecular pathways: AXL, a membrane receptor mediator of resistance to therapy. Clin Cancer Res 2016; 22 (06) 1313-1317
    CrossrefPubMedGoogle Scholar
  • 139 Breitenecker K, Hedrich V, Pupp F. et al. Synergism of the receptor tyrosine kinase Axl with ErbB receptors mediates resistance to regorafenib in hepatocellular carcinoma. Front Oncol 2023; 13: 1238883
    CrossrefPubMedGoogle Scholar
  • 140 Duan Y, Wong W, Chua SC. et al. Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression. Int J Oncol 2016; 48 (01) 358-366
    CrossrefPubMedGoogle Scholar
  • 141 Tsai CL, Chang JS, Yu MC. et al. Functional genomics identifies hepatitis-induced STAT3-TYRO3-STAT3 signaling as a potential therapeutic target of hepatoma. Clin Cancer Res 2020; 26 (05) 1185-1197
    CrossrefPubMedGoogle Scholar
  • 142 Wang W, Jia WD, Hu B, Pan YY. RAB10 overexpression promotes tumor growth and indicates poor prognosis of hepatocellular carcinoma. Oncotarget 2017; 8 (16) 26434-26447
    CrossrefPubMedGoogle Scholar
  • 143 Kabir TD, Ganda C, Brown RM. et al. A microRNA-7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma. Hepatology 2018; 67 (01) 216-231
    CrossrefPubMedGoogle Scholar
  • 144 Abou-Alfa GK, Meyer T, Cheng AL. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018; 379 (01) 54-63
    CrossrefPubMedGoogle Scholar
  • 145 Costa M, Bellosta P, Basilico C. Cleavage and release of a soluble form of the receptor tyrosine kinase ARK in vitro and in vivo. J Cell Physiol 1996; 168 (03) 737-744
    CrossrefPubMedGoogle Scholar
  • 146 Smirne C, Rigamonti C, De Benedittis C. et al. Gas6/TAM signaling components as novel biomarkers of liver fibrosis. Dis Markers 2019; 2019: 2304931
    CrossrefPubMedGoogle Scholar
  • 147 Reichl P, Fang M, Starlinger P. et al. Multicenter analysis of soluble Axl reveals diagnostic value for very early stage hepatocellular carcinoma. Int J Cancer 2015; 137 (02) 385-394
    CrossrefPubMedGoogle Scholar
  • 148 Staufer K, Dengler M, Huber H. et al. The non-invasive serum biomarker soluble Axl accurately detects advanced liver fibrosis and cirrhosis. Cell Death Dis 2017; 8 (10) e3135
    CrossrefPubMedGoogle Scholar
  • 149 Dengler M, Staufer K, Huber H. et al. Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis. Oncotarget 2017; 8 (28) 46234-46248
    CrossrefPubMedGoogle Scholar
  • 150 Bellan M, Pogliani G, Marconi C. et al. Gas6 as a putative noninvasive biomarker of hepatic fibrosis. Biomarkers Med 2016; 10 (12) 1241-1249
    CrossrefPubMedGoogle Scholar
  • 151 Bellan M, Sainaghi PP, Minh MT. et al. Gas6 as a predictor of esophageal varices in patients affected by hepatitis C virus related-chronic liver disease. Biomarkers Med 2018; 12 (01) 27-34
    CrossrefPubMedGoogle Scholar
  • 152 Staufer K, Huber H, Zessner-Spitzenberg J. et al. Gas6 in chronic liver disease-a novel blood-based biomarker for liver fibrosis. Cell Death Discov 2023; 9 (01) 282
    CrossrefPubMedGoogle Scholar
  • 153 Orme JJ, Du Y, Vanarsa K. et al. Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE. Clin Immunol 2016; 169: 58-68
    CrossrefPubMedGoogle Scholar
  • 154 Maras JS, Das S, Sharma S. et al. Iron-overload triggers ADAM-17 mediated inflammation in severe alcoholic hepatitis. Sci Rep 2018; 8 (01) 10264
    CrossrefPubMedGoogle Scholar
  • 155 Deng X, Lu J, Lehman-McKeeman LD. et al. p38 mitogen-activated protein kinase-dependent tumor necrosis factor-alpha-converting enzyme is important for liver injury in hepatotoxic interaction between lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 2008; 326 (01) 144-152
    CrossrefPubMedGoogle Scholar
  • 156 Müller M, Wetzel S, Köhn-Gaone J. et al. A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis. Oncotarget 2016; 7 (14) 17431-17441
    CrossrefPubMedGoogle Scholar
  • 157 Sharma M, Mohapatra J, Malik U. et al. Selective inhibition of tumor necrosis factor-α converting enzyme attenuates liver toxicity in a murine model of concanavalin A induced auto-immune hepatitis. Int Immunopharmacol 2013; 17 (02) 229-236
    CrossrefPubMedGoogle Scholar
  • 158 Bourd-Boittin K, Basset L, Bonnier D, L'helgoualc'h A, Samson M, Théret N. CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver. J Cell Mol Med 2009; 13 (8A): 1526-1535
    CrossrefPubMedGoogle Scholar
  • 159 McKee C, Sigala B, Soeda J. et al. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. Sci Rep 2015; 5: 8812
    CrossrefPubMedGoogle Scholar
  • 160 Fiorentino L, Vivanti A, Cavalera M. et al. Increased tumor necrosis factor α-converting enzyme activity induces insulin resistance and hepatosteatosis in mice. Hepatology 2010; 51 (01) 103-110
    CrossrefPubMedGoogle Scholar
  • 161 Flem-Karlsen K, Nyakas M, Farstad IN. et al. Soluble AXL as a marker of disease progression and survival in melanoma. PLoS One 2020; 15 (01) e0227187
    CrossrefPubMedGoogle Scholar
  • 162 Martínez-Bosch N, Cristóbal H, Iglesias M. et al. Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis. EBioMedicine 2022; 75: 103797
    CrossrefPubMedGoogle Scholar
  • 163 Song X, Wu A, Ding Z, Liang S, Zhang C. Soluble Axl is a novel diagnostic biomarker of hepatocellular carcinoma in Chinese patients with chronic hepatitis B VIRUS INFECTION. Cancer Res Treat 2020; 52 (03) 789-797
    CrossrefPubMedGoogle Scholar