CX(3)CR1 and vascular adhesion protein-1-dependent recruitment of CD16(+) monocytes across human liver sinusoidal endothelium.
The liver contains macrophages and myeloid dendritic cells (mDCs) that are critical for the regulation of hepatic inflammation. Most hepatic macrophages and mDCs are derived from monocytes recruited from the blood through poorly understood interactions with hepatic sinusoidal endothelial cells (HSECs). Human CD16(+) monocytes are thought to contain the precursor populations for tissue macrophages and mDCs. We report that CD16(+) cells localize to areas of active inflammation and fibrosis in chronic inflammatory liver disease and that a unique combination of cell surface receptors promotes the transendothelial migration of CD16(+) monocytes through human HSECs under physiological flow. CX(3)CR1 activation was the dominant pertussis-sensitive mechanism controlling transendothelial migration under flow, and expression of the CX(3)CR1 ligand CX(3)CL1 is increased on hepatic sinusoids in chronic inflammatory liver disease. Exposure of CD16(+) monocytes to immobilized purified CX(3)CL1 triggered beta1-integrin-mediated adhesion to vascular cell adhesion molecule-1 and induced the development of a migratory phenotype. Following transmigration or exposure to soluble CX(3)CL1, CD16(+) monocytes rapidly but transiently lost expression of CX(3)CR1. Adhesion and transmigration across HSECs under flow was also dependent on vascular adhesion protein-1 (VAP-1) on the HSECs.


CONCLUSIONS
Our data suggest that CD16(+) monocytes are recruited by a combination of adhesive signals involving VAP-1 and CX(3)CR1 mediated integrin-activation. Thus a novel combination of surface molecules, including VAP-1 and CX(3)CL1 promotes the recruitment of CD16(+) monocytes to the liver, allowing them to localize at sites of chronic inflammation and fibrosis.
The Liver Unit, University of Calgary Health Sciences Center, Calgary, Alberta, Canada.
Alexander I
AI
Aspinall
Stuart M
SM
Curbishley
Patricia F
PF
Lalor
Chris J
CJ
Weston
Miroslava
M
Blahova
Evaggelia
E
Liaskou
Rebecca M
RM
Adams
Andrew P
AP
Holt
David H
DH
Adams
D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology; D004727:Endothelium / Q000276:immunology; D058851:GPI-Linked Proteins; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D010641:Phenotype; D019707:Receptors, Chemokine / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D015815:Cell Adhesion Molecules; D054428:Chemokine CX3CL1; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D019707:Receptors, Chemokine; D017452:Receptors, IgG; D019010:Vascular Cell Adhesion Molecule-1; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)