Abstract
ABSTRACTClassical junctional adhesion molecules JAM-A, JAM-B and JAM-C influence vascular permeability, cell polarity as well as leukocyte recruitment and immigration into inflamed tissue. As the vasculature becomes remodelled in chronically injured, fibrotic livers we aimed to determine distribution and role of junctional adhesion molecules during this pathological process. Therefore, livers of naïve or carbon tetrachloride-treated mice were analyzed by immunohistochemistry to localize all 3 classical junctional adhesion molecules. Hepatic stellate cells and endothelial cells were isolated and subjected to immunocytochemistry and flow cytometry to determine localization and functionality of JAM-B and JAM-C. Cells were further used to perform contractility and migration assays and to study endothelial tubulogenesis and pericytic coverage by hepatic stellate cells. We found that in healthy tissue, JAM-A was ubiquitously expressed whereas JAM-B and JAM-C were restricted to the vasculature. During fibrosis, JAM-B and JAM-C levels increased in endothelial cells and JAM-C was de novo generated in myofibroblastic hepatic stellate cells. Soluble JAM-C blocked contractility but increased motility in hepatic stellate cells. Furthermore, soluble JAM-C reduced endothelial tubulogenesis and endothelial cell/stellate cell interaction. Thus, during liver fibrogenesis, JAM-B and JAM-C expression increase on the vascular endothelium. More importantly, JAM-C appears on myofibroblastic hepatic stellate cells linking them as pericytes to JAM-B positive endothelial cells. This JAM-B/JAM-C mediated interaction between endothelial cells and stellate cells stabilizes vessel walls and may control the sinusoidal diameter. Increased hepatic stellate cell contraction mediated by JAM-C/JAM-C interaction may cause intrahepatic vasoconstriction, which is a major complication in liver cirrhosis.
Highlights
Junctional adhesion molecules (JAMs) are components of tight junctions (TJ) in epithelial and endothelial cells (ECs) and as such play a role in the regulation of cell permeability, cell polarity and leukocyte transmigration
The extracellular domains form homophilic and heterophilic (JAM-B with JAM-C) interactions but bind integrins: JAM-A interacts with integrin aLb2, JAM-B binds to integrin a4b1, and JAM-C associates with integrins aMb2, aXb2 and aVb3.3 Such interactions allow heterotypic cell associations between ECs and platelets, mural cells, cancer cells or leukocytes, the latter playing an important role during tissue homeostasis and immune cell infiltration of inflamed tissue
We identified JAM-A as a broadly distributed protein expressed for example on ECs like liver sinusoidal endothelial cells (LSECs), on hepatocytes or on biliary epithelial cells
Summary
Junctional adhesion molecules (JAMs) are components of tight junctions (TJ) in epithelial and endothelial cells (ECs) and as such play a role in the regulation of cell permeability, cell polarity and leukocyte transmigration. In humans JAMs are expressed by platelets and lymphocytes They are members of an immunoglobulin super family and consist of 3 classical JAMs (JAM-A, JAM-B, JAM-C) as well as 4 related proteins (JAM-4, JAM-L, CAR, ESAM).[1,2,3] The extracellular domains form homophilic (all JAMs) and heterophilic (JAM-B with JAM-C) interactions but bind integrins: JAM-A interacts with integrin aLb2, JAM-B binds to integrin a4b1, and JAM-C associates with integrins aMb2, aXb2 and aVb3.3 Such interactions allow heterotypic cell associations between ECs and platelets, mural cells, cancer cells or leukocytes, the latter playing an important role during tissue homeostasis and immune cell infiltration of inflamed tissue. Tissue inflammation can induce the redistribution of JAMs to the luminal side of ECs, resulting in increased arrest of leukocytes on the endothelial layer, followed by enhanced transendothelial migration.[1,2,3,4,5,6]
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