Lymphocyte traffic through sinusoidal endothelial cells is regulated by hepatocytes

Abstract

Crosstalk between hepatic sinusoidal ECs and closely juxtaposed hepatocytes via vascular endothelial growth factor is essential for the maintenance of sinusoidal endothelial growth and differentiation. We propose that paracrine interactions between endothelial cells and hepatocytes also may be responsible for the unique complement of adhesion receptors expressed on sinusoidal endothelium that regulate the recruitment of lymphocytes into the liver. To address this hypothesis, we developed an in vitro model of the hepatic sinusoid in which flowing lymphocytes could interact with hepatic endothelium conditioned by the presence of hepatocytes. Human hepatic sinusoidal endothelial cells cocultured with hepatocytes were activated so that they supported the adhesion of lymphocytes at levels equivalent to those seen on endothelium stimulated with the inflammatory cytokine tumour necrosis factor-␤.

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…It is noteworthy that cross-talk between liver cells and other cell types, such as leukocytes, may be of great importance for activity and progression of NAFLD. Indeed, exchange and processing of proinflammatory signaling molecules seems to be essential for the progression of NAFLD and its associated architectural changes [i.e., fibrosis due to altered extracellular matrix production of transformed stellate cells to (myo)fibroblastic cells] (Diehl, 2002;Edwards et al, 2005;Bilzer et al, 2006;.…”

“…From in vitro experiments it could be demonstrated that endothelial cells of the sinusoid required coculture with hepatocytes for the regulation of vascular cell adhesion molecule, ICAM, CD31, and E-selectin expression (Edwards et al, 2005). The cross-talk between these two cell types may be grossly changed during inflammation.…”

“…In NAFLD, leukocytes adhere and migrate through the endothelial barrier to the space of Disse toward the liver cell parenchyma (Adams et al, 1994;Lalor et al, 2002) and are directed by cell adhesion molecules and chemotactic molecules. Nonetheless, it remains to be determined whether metabolically compromised and steatotic hepatocytes provide the initial signal for sinusoidal infiltration of immuno-component cells or whether other factors such as compression of the sinusoid as a result of hepatocyte enlargement foster leukocyte invasion into the fatty liver (Edwards et al, 2005;Bilzer et al, 2006;Thabut et al, 2007). In addition, endothelial dysfunction at the sinusoid may be a further confounder in NAFLD (i.e., due to increased systemic level of circulatory cytokines and LPS, increased levels of ROS, VEGF expression) (Spolarics, 1998).…”

Key role of liver sinusoidal endothelial cells in liver fibrosis

“…A study by Bonder et al found that Th1 and Th2 cells respectively recruit and use α4β1-integrin and vascular adhesion protein (VAP)-1,two cell surface molecules expressed on LSECs, to adhere to liver sinusoids during liver fibrosis (51) (Figure 3). In addition, LSECs can be activated, express adhesion molecules, and synthesize chemokines that are exposed on their luminal surface during inflammation whileVAP-1 can be upregulated by chronic inflammation (52)(53)(54)(55). However, the relationship between T cells and defenestration of LSECs during hepatic sinusoid capillarization still needs to be explained further.…”

Inhibition of Semicarbazide-Sensitive Amine Oxidases Decreases Lymphocyte Infiltration in the Early Phases of Rat Liver Allograft Rejection

“…Moreover, inhibition of SSAO decreases lymphocyte adhesion to hepatic endothelial cells in vitro (10). VAP-l is also shed from the cell surface into serum.…”