title: Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver.
abstract: Monocytes are versatile cells that can fulfill proinflammatory and anti-inflammatory functions when recruited to the liver. Recruited monocytes differentiate into tissue macrophages and dendritic cells, which sample antigens and migrate to lymph nodes to elicit T-cell responses. The signals that determine monocyte differentiation and the role of hepatic sinusoidal endothelial cells (HSECs) in this process are poorly understood. HSECs are known to modulate T-cell activation, which led us to investigate whether transendothelial migration of monocytes across HSECs influences their phenotype and function. Subsets of blood-derived monocytes were allowed to transmigrate across human HSECs into a collagen matrix. Most migrated cells remained in the subendothelial matrix, but ~10% underwent spontaneous basal to apical transendothelial migration. The maturation, cytokine secretion, and T-cell stimulatory capacity of reverse transmigrating (RT) and subendothelial (SE) monocytes were compared. SE monocytes were mainly CD16(-) , whereas 75%-80% of RT monocytes were CD16(+) . SE monocytes derived from the CD14(++) CD16(-) subset and exhibited high phagocytic activity, whereas RT monocytes originated from CD14(++) CD16(+) and CD14(+) CD16(++) monocytes, displayed an immature dendritic cell-like phenotype (CD11c(pos) HLA-DR(pos) CD80lo CD86lo ), and expressed higher levels of chemokine (C-C motif) receptor 8. Consistent with a dendritic cell phenotype, RT monocytes secreted inflammatory cytokines and induced antigen-specific CD4(+) T-cell activation. In contrast, SE monocytes suppressed T-cell proliferation and activation and exhibited endotoxin tolerance. Transcriptome analysis underscored the functional differences between SE and RT monocytes.
  
  
  CONCLUSIONS
  Migration across HSECs shapes the subsequent fate of monocytes, giving rise to anergic macrophage-like cells in tissue and the release of immunocompetent pre-dendritic cells into the circulation.
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.|Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.|Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.|Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University of Jena, Jena, Germany.
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Weston
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Curbishley
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Evaggelia
authors.initials: E
authors.lastname: Liaskou
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: Ka-Kit
authors.initials: KK
authors.lastname: Li
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.|Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Yazid J
authors.initials: YJ
authors.lastname: Resheq
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Badenhorst
authors.affiliation: National Institute for Health Research Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000166:cytology* / Q000276:immunology*; D009000:Monocytes / Q000502:physiology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*