Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice

Edith Hintermann, Monika Bayer, Clara Benedetta Conti, Sina Fuchs, Michel Fausther, Patrick S Leung, Michel Aurrand-Lions, Richard Taubert, Josef M. Pfeilschifter, Mireen Friedrich-Rust, Detlef Schuppan, Jonathan A. Dranoff, M. Eric Gershwin, Michael P. Manns, Beat A. Imhof, Urs Christen

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively. Therefore, localization and function of JAM-B and JAM-C were investigated in three mouse models of autoimmune-driven liver inflammation. A PBC-like disease was induced by immunization with 2-octynoic acid-BSA conjugate, which resulted in the upregulation of both JAMs in fibrotic portal triads. Analysis of a murine model of PSC revealed a role of JAM-C in PF cell-cell adhesion and contractility. In mice suffering from AIH, endothelial cells increased JAM-B level and HSCs and capsular fibroblasts became JAM-C-positive. Most importantly, AIH-mediated liver fibrosis was reduced in JAM-B−/− mice or when JAM-C was blocked by soluble recombinant JAM-C. Interestingly, loss of JAM-B/JAM-C function had no effect on leukocyte infiltration, suggesting that the well-documented function of JAMs in leukocyte recruitment to inflamed tissue was not effective in the tested chronic models. This might be different in patients and may even be complicated by the fact that human leukocytes express JAM-C. Our findings delineate JAM-C as a mediator of myofibroblast-operated contraction of the liver capsule, intrahepatic vasoconstriction and bile duct stricture. Due to its potential to interact heterophilically with endothelial JAM-B, JAM-C supports also HSC/PF mural cell function. Together, these properties allow JAM-B and JAM-C to actively participate in vascular remodeling associated with liver/biliary fibrosis and suggest them as valuable targets for anti-fibrosis therapies.

Original languageEnglish (US)
JournalJournal of Autoimmunity
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Junctional Adhesion Molecule B
Junctional Adhesion Molecule C
Junctional Adhesion Molecules
Liver Cirrhosis
Hepatic Stellate Cells
Autoimmune Hepatitis
Fibroblasts
Sclerosing Cholangitis
Leukocytes
Cholangitis
Endothelial Cells
Liver
Fibrosis

Keywords

  • Autoimmune liver disease
  • Biliary fibrosis
  • Hepatic fibrosis
  • Mural cell
  • Myofibroblast

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice. / Hintermann, Edith; Bayer, Monika; Conti, Clara Benedetta; Fuchs, Sina; Fausther, Michel; Leung, Patrick S; Aurrand-Lions, Michel; Taubert, Richard; Pfeilschifter, Josef M.; Friedrich-Rust, Mireen; Schuppan, Detlef; Dranoff, Jonathan A.; Gershwin, M. Eric; Manns, Michael P.; Imhof, Beat A.; Christen, Urs.

In: Journal of Autoimmunity, 01.01.2018.

Research output: Contribution to journalArticle

Hintermann, E, Bayer, M, Conti, CB, Fuchs, S, Fausther, M, Leung, PS, Aurrand-Lions, M, Taubert, R, Pfeilschifter, JM, Friedrich-Rust, M, Schuppan, D, Dranoff, JA, Gershwin, ME, Manns, MP, Imhof, BA & Christen, U 2018, 'Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice', Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2018.05.001
Hintermann, Edith ; Bayer, Monika ; Conti, Clara Benedetta ; Fuchs, Sina ; Fausther, Michel ; Leung, Patrick S ; Aurrand-Lions, Michel ; Taubert, Richard ; Pfeilschifter, Josef M. ; Friedrich-Rust, Mireen ; Schuppan, Detlef ; Dranoff, Jonathan A. ; Gershwin, M. Eric ; Manns, Michael P. ; Imhof, Beat A. ; Christen, Urs. / Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice. In: Journal of Autoimmunity. 2018.
@article{726c07013e0344f7a176fc62c6650329,
title = "Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice",
abstract = "Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively. Therefore, localization and function of JAM-B and JAM-C were investigated in three mouse models of autoimmune-driven liver inflammation. A PBC-like disease was induced by immunization with 2-octynoic acid-BSA conjugate, which resulted in the upregulation of both JAMs in fibrotic portal triads. Analysis of a murine model of PSC revealed a role of JAM-C in PF cell-cell adhesion and contractility. In mice suffering from AIH, endothelial cells increased JAM-B level and HSCs and capsular fibroblasts became JAM-C-positive. Most importantly, AIH-mediated liver fibrosis was reduced in JAM-B−/− mice or when JAM-C was blocked by soluble recombinant JAM-C. Interestingly, loss of JAM-B/JAM-C function had no effect on leukocyte infiltration, suggesting that the well-documented function of JAMs in leukocyte recruitment to inflamed tissue was not effective in the tested chronic models. This might be different in patients and may even be complicated by the fact that human leukocytes express JAM-C. Our findings delineate JAM-C as a mediator of myofibroblast-operated contraction of the liver capsule, intrahepatic vasoconstriction and bile duct stricture. Due to its potential to interact heterophilically with endothelial JAM-B, JAM-C supports also HSC/PF mural cell function. Together, these properties allow JAM-B and JAM-C to actively participate in vascular remodeling associated with liver/biliary fibrosis and suggest them as valuable targets for anti-fibrosis therapies.",
keywords = "Autoimmune liver disease, Biliary fibrosis, Hepatic fibrosis, Mural cell, Myofibroblast",
author = "Edith Hintermann and Monika Bayer and Conti, {Clara Benedetta} and Sina Fuchs and Michel Fausther and Leung, {Patrick S} and Michel Aurrand-Lions and Richard Taubert and Pfeilschifter, {Josef M.} and Mireen Friedrich-Rust and Detlef Schuppan and Dranoff, {Jonathan A.} and Gershwin, {M. Eric} and Manns, {Michael P.} and Imhof, {Beat A.} and Urs Christen",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jaut.2018.05.001",
language = "English (US)",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice

AU - Hintermann, Edith

AU - Bayer, Monika

AU - Conti, Clara Benedetta

AU - Fuchs, Sina

AU - Fausther, Michel

AU - Leung, Patrick S

AU - Aurrand-Lions, Michel

AU - Taubert, Richard

AU - Pfeilschifter, Josef M.

AU - Friedrich-Rust, Mireen

AU - Schuppan, Detlef

AU - Dranoff, Jonathan A.

AU - Gershwin, M. Eric

AU - Manns, Michael P.

AU - Imhof, Beat A.

AU - Christen, Urs

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively. Therefore, localization and function of JAM-B and JAM-C were investigated in three mouse models of autoimmune-driven liver inflammation. A PBC-like disease was induced by immunization with 2-octynoic acid-BSA conjugate, which resulted in the upregulation of both JAMs in fibrotic portal triads. Analysis of a murine model of PSC revealed a role of JAM-C in PF cell-cell adhesion and contractility. In mice suffering from AIH, endothelial cells increased JAM-B level and HSCs and capsular fibroblasts became JAM-C-positive. Most importantly, AIH-mediated liver fibrosis was reduced in JAM-B−/− mice or when JAM-C was blocked by soluble recombinant JAM-C. Interestingly, loss of JAM-B/JAM-C function had no effect on leukocyte infiltration, suggesting that the well-documented function of JAMs in leukocyte recruitment to inflamed tissue was not effective in the tested chronic models. This might be different in patients and may even be complicated by the fact that human leukocytes express JAM-C. Our findings delineate JAM-C as a mediator of myofibroblast-operated contraction of the liver capsule, intrahepatic vasoconstriction and bile duct stricture. Due to its potential to interact heterophilically with endothelial JAM-B, JAM-C supports also HSC/PF mural cell function. Together, these properties allow JAM-B and JAM-C to actively participate in vascular remodeling associated with liver/biliary fibrosis and suggest them as valuable targets for anti-fibrosis therapies.

AB - Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and JAM-C by endothelial cells and de novo synthesis of JAM-C by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) display elevated levels of JAM-C on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively. Therefore, localization and function of JAM-B and JAM-C were investigated in three mouse models of autoimmune-driven liver inflammation. A PBC-like disease was induced by immunization with 2-octynoic acid-BSA conjugate, which resulted in the upregulation of both JAMs in fibrotic portal triads. Analysis of a murine model of PSC revealed a role of JAM-C in PF cell-cell adhesion and contractility. In mice suffering from AIH, endothelial cells increased JAM-B level and HSCs and capsular fibroblasts became JAM-C-positive. Most importantly, AIH-mediated liver fibrosis was reduced in JAM-B−/− mice or when JAM-C was blocked by soluble recombinant JAM-C. Interestingly, loss of JAM-B/JAM-C function had no effect on leukocyte infiltration, suggesting that the well-documented function of JAMs in leukocyte recruitment to inflamed tissue was not effective in the tested chronic models. This might be different in patients and may even be complicated by the fact that human leukocytes express JAM-C. Our findings delineate JAM-C as a mediator of myofibroblast-operated contraction of the liver capsule, intrahepatic vasoconstriction and bile duct stricture. Due to its potential to interact heterophilically with endothelial JAM-B, JAM-C supports also HSC/PF mural cell function. Together, these properties allow JAM-B and JAM-C to actively participate in vascular remodeling associated with liver/biliary fibrosis and suggest them as valuable targets for anti-fibrosis therapies.

KW - Autoimmune liver disease

KW - Biliary fibrosis

KW - Hepatic fibrosis

KW - Mural cell

KW - Myofibroblast

UR - http://www.scopus.com/inward/record.url?scp=85046719939&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046719939&partnerID=8YFLogxK

U2 - 10.1016/j.jaut.2018.05.001

DO - 10.1016/j.jaut.2018.05.001

M3 - Article

C2 - 29753567

AN - SCOPUS:85046719939

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

ER -