Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver

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BACKGROUND: Monocytes are versatile cells that can fulfil pro- 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 (HSEC) in this process are poorly understood. HSEC are known to modulate T-cell activation leading us to investigate whether transendothelial migration (TEM) of monocytes across HSEC influences their phenotype and function.

MATERIALS AND METHODS: Subsets of blood-derived monocytes were allowed to transmigrate across human HSEC into a collagen matrix. Most migrated cells remained in the subendothelial matrix but ∼10% underwent spontaneous basal to apical TEM. The maturation, cytokine secretion and T-cell stimulatory capacity of reverse transmigrating (RT) and subendothelial (SE) monocytes were compared.

RESULTS: 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 DC-like phenotype (CD11c(pos) HLA-DR(pos) CD80lo CD86lo ) and expressed higher levels of CCR8. Consistent with a DC-phenotype RT-monocytes secreted inflammatory cytokines and induced Ag-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 HSEC shapes the subsequent fate of monocytes giving rise to anergic macrophage-like cells in tissue and the release of immunocompetent pre-DCs into the circulation. This article is protected by copyright. All rights reserved.

Bibliographic note

© 2015 by the American Association for the Study of Liver Diseases.


Original languageEnglish
Early online date16 Oct 2015
Publication statusPublished - 2015