Apicobasal Polarity Controls Lymphocyte Adhesion to Hepatic Epithelial Cells

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. [Display omitted] •Loss of apicobasal polarity increases lymphocyte adhesion to hepatic epithelial cells•The adhesion receptor ICAM-1 is apically confined in polarized hepatic cells•Upon loss of cell polarity, ICAM-1 is exposed and interacts with lymphocytes•Basolateral-to-apical transport prevents ICAM-1 basolateral localization Many epithelial pathologies induce loss of apicobasal polarity. Epithelial intercellular adhesion molecule 1 (ICAM-1) mediates lymphocyte adhesion to hepatic epithelial cells. Reglero-Real et al. now show that polarized hepatocytes and bile duct epithelial cells confine ICAM-1 to their apical membrane domains, which are less accessible to circulating immune cells. Upon depolarization, apical ICAM-1 is exposed and increases lymphocyte binding. Epithelial apicobasal polarity thus helps the immune system to discriminate between normal and depolarized, dysfunctional hepatic cells exposing their adhesion machinery.