title: Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines.
abstract: Transmigration through the liver endothelium is a prerequisite for the homeostatic balance of intrahepatic T cells and a key regulator of inflammatory processes within the liver. Extravasation into the liver parenchyma is regulated by the distinct expression patterns of adhesion molecules and chemokines and their receptors on the lymphocyte and endothelial cell surface. In the present study, we investigated whether liver sinusoidal endothelial cells (LSEC) inhibit or support the chemokine-driven transmigration and differentially influence the transmigration of pro-inflammatory or anti-inflammatory CD4(+) T cells, indicating a mechanism of hepatic immunoregulation. Finally, the results shed light on the molecular mechanisms by which LSEC modulate chemokine-dependent transmigration. LSEC significantly enhanced the chemotactic effect of CXC-motif chemokine ligand 12 (CXCL12) and CXCL9, but not of CXCL16 or CCL20, on naive and memory CD4(+) T cells of a T helper 1, T helper 2, or interleukin-10-producing phenotype. In contrast, brain and lymphatic endothelioma cells and ex vivo isolated lung endothelia inhibited chemokine-driven transmigration. As for the molecular mechanisms, chemokine-induced activation of LSEC was excluded by blockage of G(i)-protein-coupled signaling and the use of knockout mice. After preincubation of CXCL12 to the basal side, LSEC took up CXCL12 and enhanced transmigration as efficiently as in the presence of the soluble chemokine. Blockage of transcytosis in LSEC significantly inhibited this effect, and this suggested that chemokines taken up from the basolateral side and presented on the luminal side of endothelial cells trigger T cell transmigration.
  
  
  CONCLUSIONS
  Our findings demonstrate a unique capacity of LSEC to present chemokines to circulating lymphocytes and highlight the importance of endothelial cells for the in vivo effects of chemokines. Chemokine presentation by LSEC could provide a future therapeutic target for inhibiting lymphocyte immigration and suppressing hepatic inflammation.
authors.affiliation: Medizinische Klinik I, Campus Charité Benjamin Franklin, Berlin, Germany.
authors.forename: Arnhild
authors.initials: A
authors.lastname: Schrage
authors.forename: Katja
authors.initials: K
authors.lastname: Wechsung
authors.forename: Katrin
authors.initials: K
authors.lastname: Neumann
authors.forename: Michael
authors.initials: M
authors.lastname: Schumann
authors.forename: Jörg-Dieter
authors.initials: JD
authors.lastname: Schulzke
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Katja
authors.initials: K
authors.lastname: Klugewitz
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D054370:Chemokine CXCL9 / Q000378:metabolism* / Q000494:pharmacology; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D005260:Female; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D054377:Chemokine CXCL12; D054370:Chemokine CXCL9; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3