title: Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver.
abstract: Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4(+) T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL)9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4(+) T cells expressing the CXC chemokine receptor (CXCR)3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC) which represent the first contact site for T-cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin-coated vesicles to CD4(+) T cells leading to enhanced transmigration of CXCR4(+) total CD4(+) T cells and CXCR3(+) effector/memory CD4(+) T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4(+) T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4(+) T-cell transmigration in vitro as well as migration of CD4(+) T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3(+) CD4(+) T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4- and clathrin-dependent intracellular transport mechanisms thereby contributing to the hepatic recruitment of CD4(+) T-cell populations during immune surveillance and liver inflammation.
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Research Center Immunosciences, Charité-Universitätsmedizin, Berlin, Germany; Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Neumann
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Research Center Immunosciences, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Erben
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Kruse
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Wechsung
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumann
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Klugewitz
authors.affiliation: Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité-Universitätsmedizin, Berlin, Germany; German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheffold
authors.affiliation: Department of Medicine I for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany; Research Center Immunosciences, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D054370:Chemokine CXCL9 / Q000378:metabolism*; D002746:Chlorpromazine / Q000494:pharmacology; D002966:Clathrin / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006505:Hepatitis / Q000276:immunology / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL
chemical_list: D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; D054370:Chemokine CXCL9; D002966:Clathrin; D018836:Inflammation Mediators; D002746:Chlorpromazine