Abstract
The recruitment of lymphocytes via the hepatic sinusoidal channels and positioning within liver tissue is a critical event in the development and persistence of chronic inflammatory liver diseases. The hepatic sinusoid is a unique vascular bed lined by hepatic sinusoidal endothelial cells (HSECs), a functionally and phenotypically distinct subpopulation of endothelial cells. Using flow‐based adhesion assays to study the migration of lymphocytes across primary human HSECs, we found that lymphocytes enter into HSECs, confirmed by electron microscopy demonstrating clear intracellular localization of lymphocytes in vitro and by studies in human liver tissues. Stimulation by interferon‐γ increased intracellular localization of lymphocytes within HSECs. Furthermore, using confocal imaging and time‐lapse recordings, we demonstrated “intracellular crawling” of lymphocytes entering into one endothelial cell from another. This required the expression of intracellular adhesion molecule‐1 and stabilin‐1 and was facilitated by the junctional complexes between HSECs. Conclusion: Lymphocyte migration is facilitated by the unique structure of HSECs. Intracellular crawling may contribute to optimal lymphocyte positioning in liver tissue during chronic hepatitis. (Hepatology 2017;65:294‐309).
Highlights
Human Liver Sinusoidal Endothelial Cells Promote Intracellular Crawling of Lymphocytes During Recruitment: A New Step in Migration
The extravasation occurs within the hepatic sinusoidal channels in contrast to the postcapillary venules as seen in most other organs.[8,9] These channels are characterized by a low Abbreviations: CLEVER-1, common lymphathic endothelial and vascular endothelial receptor-1; HSEC, human sinusoidal endothelial cell; HUVEC, human umbilical vein endothelial cells; ICAM-1, intracellular adhesion molecule-1; IFNc, interferon-c; JAM-A, junctional adhesion molecule-A; PDL1, programmed death ligand-1; TNFa, tumor necrosis factor a; ZO-1, zona occludens-1
Lymphocyte recruitment is initiated within the hepatic sinusoids,(8) which are lined by specialized endothelia characterized by a unique phenotypic expression, including liver/ lymph node–specific intercellular adhesion molecule3-grabbing integrin and the scavenger receptor stabilin-1 (Fig. 1B).(16) Using flow adhesion assays with primary HSECs, we recently reported that a proportion of lymphocytes use a transcellular route to cross sinusoidal endothelium.[12]. To assess in human tissue, sections of livers from patients with chronic liver disease were visualized by confocal microscopy and immunofluorescent labeling
Summary
Human Liver Sinusoidal Endothelial Cells Promote Intracellular Crawling of Lymphocytes During Recruitment: A New Step in Migration. Chronic inflammation is a major cause of global morbidity and mortality, often leading to tissue fibrosis and organ failure, and is a recognized risk factor for carcinogenesis.[1,2,3,4] It is characterized by the recruitment of immune cells into organs via their interaction with endothelial cells followed by their positioning in strategic locations within the tissue.[5] This is seen in most adult liver diseases that are driven by chronic inflammation, where leukocytes are recruited via specialized channels known as sinusoids, which are lined by hepatic sinusoidal endothelial cells (HSECs).(6) This influx of immune cells often leads to lymphoid aggregates/follicles around the portal tract in a range of liver diseases.[7]. The extravasation occurs within the hepatic sinusoidal channels in contrast to the postcapillary venules as seen in most other organs.[8,9] These channels are characterized by a low Abbreviations: CLEVER-1, common lymphathic endothelial and vascular endothelial receptor-1; HSEC, human sinusoidal endothelial cell; HUVEC, human umbilical vein endothelial cells; ICAM-1, intracellular adhesion molecule-1; IFNc, interferon-c; JAM-A, junctional adhesion molecule-A; PDL1, programmed death ligand-1; TNFa, tumor necrosis factor a; ZO-1, zona occludens-1
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