Zelluläre Wechselwirkungen in der fibrotischen Leber: Adhesionsmoleküle JAM-B und JAM-C als Vermittler der Interaktion zwischen Sinusoiden und Perizyten.
Immunologie
Zellbiologie
Zusammenfassung der Projektergebnisse
Fibrosis remains a serious health concern in patients with chronic liver disease. Our studies demonstrate that chemically induced chronic murine liver injury, as well as autoimmune processes which result in fibrotic liver damage in mice and in men trigger increased expression of junctional adhesion molecule (JAM) JAM-C. Biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) displayed elevated levels of JAM-C on portal fibroblasts (PFs), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and cholangiocytes, whereas smooth muscle cells expressed JAM-C constitutively. Similar findings were made in the tested mouse models of AIH, PBC and PSC. Importantly, blockade of JAM-C by soluble recombinant JAM-C protein prevented liver fibrosis in the Ad-2D6-induced mouse model of AIH. JAM-B was not detected in patient biopsies with the available tools. However, in the fibrotic mouse liver JAM-B was upregulated on LSECs and its absence protected the JAM-B-/- mouse from Ad-2D6-induced liver fibrosis. JAMs are located at tight junctions of epithelial and endothelial cells (ECs), are variably expressed by smooth muscle cells, platelets, erythrocytes and leukocytes in humans and by fibroblasts and smooth muscle cells in the mouse. This multitude of interactions allows homotypic cell associations of epithelial cells and ECs and heterotypic cell-cell binding. Hence, JAMs are involved in the regulation of diverse functions like cell permeability, polarity, and proliferation, angiogenesis or leukocyte transmigration during tissue inflammation. Surprisingly, we could not detect differences in the number of Ad-2D6-induced liver-infiltrating leukocytes when we compared wildtype mice with JAM-B-/- mice (complete absence of JAM-B) or pHHNS- JAM-C+ mice (endothelial JAM-C overexpression) or when mice were treated with soluble JAM- C-FLAG protein or FLAG peptide. Other adhesion molecules like VCAM or ICAM may therefore be of higher importance for leukocyte recruitment in the Ad-2D6-induced AIH model. Whereas JAM-mediated EC/leukocyte interactions have been investigated very intensively, EC/pericyte and homotypic pericyte interactions have caught less attention. Our murine data show an involvement of JAM-B and JAM-C in LSEC/myofibroblast association, supporting LSEC tube formation. In myofibroblastic HSCs and PFs JAM-C was expressed in cell-cell adhesion complexes at the tip of stress fibers and its blockade reduced cell-cell contact formation and contractility in vitro. Myofibroblasts in the portal tract surround bile ducts and sinusoids. Fibrosis-triggered upregulation of JAM-C expression and contractility may provide mechanical stability to bile ducts and portal vasculature and limit damage caused by increased ductal pressure. Alternatively, the increase in PF and HSC contractility itself may be the cause of bile duct and sinusoid constriction as observed in autoimmune liver diseases. Since mechanical forces can regulate transcription of genes involved in myofibroblast differentiation, a reduction in transmitting mechanical forces due to reduced JAM-C homophilic interaction may slow down HSC differentiation and associated cellular functions like the production of fibrotic extracellular matrix. Therefore, application of soluble recombinant JAM-C protein during Ad-2D6-triggered autoimmune liver inflammation may have led to diminished HSC differentiation, as well as reduced fibrosis-associated angiogenesis and sinusoidal remodeling, explaining the observed decline in liver stiffness. Chronic liver damage in men is not only autoimmune-driven but occurs also due to nonalcoholic steatohepatitis (NASH), alcohol abuse, viral hepatitis or schistosomiasis and may in general result in increased JAM expression on relevant hepatic epithelial and endothelial cells as well as myofibroblasts, influencing cell-cell interactions during fibrogenesis. Our data suggest that blockade of JAM-B and/or JAM-C interaction may represent a general strategy to antagonize fibrosis in liver disease. However, one has to bear in mind that in men infiltrating T lymphocytes, natural killer cells or dendritic cells express JAM-C as well. Interfering with leukocyte migration may have unexpected effects on disease outcome. Despite such challenges, new antifibrotic therapies are needed as to date no effective treatment is available. Thus, inhibiting pericyte homotypic and/or heterotypic cellular interactions might represent a novel strategy.
Projektbezogene Publikationen (Auswahl)
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(2015) An update on animal models of autoimmune hepatitis: Are we there yet? Curr. Pharm. Des. 21(18): 2391-400
Christen U. and Hintermann E.
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(2016) Immunopathogenic mechanisms of autoimmune hepatitis: How much do we know from animal models? Int. J. Mol. Sci. 17(12), 2007
Christen U. and Hintermann E.
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(2016) Murine junctional adhesion molecules JAM-B and JAM-C mediate endothelial and stellate cell interactions during hepatic fibrosis. Cell Adh. Migr. 10(4): 419-33
Hintermann E., Bayer M., Ehser J., Aurrand-Lions M., Pfeilschifter J.M., Imhof B.A., Christen U.
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(2016) Nonalcoholic fatty liver disease (NAFLD) potentiates autoimmune hepatitis in the CYP2D6 mouse model. J. Autoimmun. 69:51-58
Müller P., Messmer M., Bayer M., Pfeilschifter J.M., Hintermann E., Christen U.
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(2018) Autoantibodies in autoimmune hepatitis: Can epitopes tell us about the etiology of the disease? Front. Immunol. 9: 163
Christen U. and Hintermann E.
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(2018) Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice. J. Autoimmun. 91: 83-96
Hintermann E., Bayer M., Conti C.B., Fuchs S., Fausther M., Leung P.S., Aurrand-Lions M., Taubert R., Pfeilschifter J.M., Friedrich-Rust M., Schuppan D., Dranoff J.A., Gershwin M.E., Manns M.P., Imhof B.A., Christen U.
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(2019) Pathogens and autoimmune hepatitis. Clin. Exp. Immunol. 195(1):35-51
Christen U. and Hintermann E.
