2)42, 43 CD16+ monocytes in blood showed homogenous intermediate

2).42, 43 CD16+ monocytes in blood showed homogenous intermediate levels of CX3CR1, whereas mDCs isolated from the liver included CX3CR1high cells and a population that expressed levels comparable to blood CD16+ monocytes. CD16+ monocytes lost CX3CR1 surface expression during the check details process of transmigration and as a consequence of receptor engagement by CX3CL1. Exposure to soluble CX3CL1

in vitro resulted in a profound but transient loss of cell surface CX3CR1 and could explain why prior exposure to soluble CX3CL1 prevents transendothelial migration; a similar effect has been reported for other chemokine receptors.44 Thus, CX3CL1 must be appropriately retained and presented on endothelium to function efficiently. Re-expression of CX3CR1 after cells have been recruited to the liver parenchyma could be important for their onward migration to areas of portal or lobular inflammation, where CX3CL1 is also strongly expressed42 (Fig. 2). In addition to CX3CL1 and VCAM-1, VAP-1 was involved in CD16+ monocyte transendothelial migration under flow. VAP-1 belongs to an expanding family of ectoenzymes involved in cellular trafficking.45 VAP-1 is present on liver sinusoidal endothelium,

where it has been implicated in lymphocyte recruitment in humans and rodents.27, 35, 36 Soluble VAP-1 is detected at high levels in the serum of patients with Terminal deoxynucleotidyl transferase chronic liver disease, but not other inflammatory conditions such as rheumatoid arthritis.46, 47 VAP-1 can mediate sialic acid-dependent see more tethering and transendothelial migration of lymphocytes on sinusoidal endothelium.27, 48 This is the first

time that VAP-1 has been implicated in monocyte transendothelial migration, although reduced monocyte recruitment to inflammatory sites has been reported in mice after VAP-1 blockade.49 We found that VAP-1 was involved in both adhesion and transendothelial migration. The combination of immobilized CX3CL1 and VAP-1 proteins on their own failed to support significant levels of adhesion, suggesting that VAP-1 operates in conjunction with other receptors to mediate transendothelial migration, consistent with data showing that enzymatic activity of VAP-1 modulates the expression of other adhesion molecules34 (Fig. 5). These findings add to an evolving body of literature that implicates VAP-1 as an important molecule in leukocyte transmigration across hepatic sinusoidal endothelium in vitro and in vivo and provide further evidence that the sinusoidal bed uses distinct combinations of molecules to recruit leukocytes to the liver parenchyma.25, 34-36, 50 The role of VAP-1 in transendothelial migration is particularly interesting.

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