title: Apicobasal polarity controls lymphocyte adhesion to hepatic epithelial cells.
abstract: Loss of apicobasal polarity is a hallmark of epithelial pathologies. Leukocyte infiltration and crosstalk with dysfunctional epithelial barriers are crucial for the inflammatory response. Here, we show that apicobasal architecture regulates the adhesion between hepatic epithelial cells and lymphocytes. Polarized hepatocytes and epithelium from bile ducts segregate the intercellular adhesion molecule 1 (ICAM-1) adhesion receptor onto their apical, microvilli-rich membranes, which are less accessible by circulating immune cells. Upon cell depolarization, hepatic ICAM-1 becomes exposed and increases lymphocyte binding. Polarized hepatic cells prevent ICAM-1 exposure to lymphocytes by redirecting basolateral ICAM-1 to apical domains. Loss of ICAM-1 polarity occurs in human inflammatory liver diseases and can be induced by the inflammatory cytokine tumor necrosis factor alpha (TNF-α). We propose that adhesion receptor polarization is a parenchymal immune checkpoint that allows functional epithelium to hamper leukocyte binding. This contributes to the haptotactic guidance of leukocytes toward neighboring damaged or chronically inflamed epithelial cells that expose their adhesion machinery.
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Reglero-Real
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Álvarez-Varela
authors.affiliation: Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Cernuda-Morollón
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Feito
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Marcos-Ramiro
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Fernández-Martín
authors.affiliation: Unidad de Hepatología Experimental, Centro de Investigación, Hospital La Fe, 46026 Valencia, Spain; Centro de Investigación Biomédica en Red para Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Gómez-Lechón
authors.affiliation: Instituto de Biomedicina de Sevilla (IBiS) Hospital Universitario Virgen del Rocio/IBiS/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Muntané
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: Centro de Investigación Biomédica en Red para Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; Unidad Biología Molecular, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Majano
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Correas
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Alonso
authors.affiliation: Centro de Biología Molecular Severo Ochoa. Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28049 Madrid, Spain. Electronic address: jmillan@cbm.csic.es.
authors.forename: Jaime
authors.initials: J
authors.lastname: Millán
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000502:physiology; D006515:Hepatitis B virus / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D018799:Intercellular Adhesion Molecule-1; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D020764:cdc42 GTP-Binding Protein; D000099149:Ezrin; C071776:radixin