JAM‐A is a multifaceted regulator in hepatic fibrogenesis, supporting LSEC integrity and stellate cell quiescence

Background and Aims Leukocyte infiltration is a hallmark of hepatic inflammation. The Junctional Adhesion Molecule A (JAM‐A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver...

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Published in:Liver international 2022-05, Vol.42 (5), p.1185-1203
Main Authors: Brozat, Jonathan F., Brandt, Elisa F., Stark, Myriam, Fischer, Petra, Wirtz, Theresa H., Flaßhove, Alexander, Rodenhausen, Aaron N., Vajen, Tanja, Heinzmann, Alexandra C. A., Schmitz, Sophia M.‐T., Abu Jhaisha, Samira, Röth, Anjali A., Koenen, Rory R., Sahin, Hacer, Trautwein, Christian, Berres, Marie‐Luise
Format: Article
Language:English
Subjects:
Adhesion
Animals
Bone marrow
Carbon tetrachloride
CCL4 protein
CD11b antigen
Cell activation
Cell culture
cell migration
Endothelial cells
Endothelial Cells - metabolism
Extravasation
Fibrosis
Gene expression
Hedgehog genes
Hedgehog protein
Hedgehog Proteins - metabolism
Hepatic Stellate Cells - metabolism
Hepatocytes
HSC activation
Humans
Immune system
In vivo methods and tests
Infiltration
Intestine
Junctional Adhesion Molecule A - metabolism
junctional adhesion molecules
Leukocytes
Liver
Liver - pathology
Liver Cirrhosis - pathology
liver fibrosis
Macrophages
Mice
Mice, Inbred C57BL
Monocytes
Phenotypes
Shear stress
Sine waves
sinusoidal capillarization
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Summary:Background and Aims Leukocyte infiltration is a hallmark of hepatic inflammation. The Junctional Adhesion Molecule A (JAM‐A) is a crucial regulator of leukocyte extravasation and is upregulated in human viral fibrosis. Reduced shear stress within hepatic sinusoids and the specific phenotype of liver sinusoidal endothelial cells (LSEC) cumulate in differing adhesion characteristics during liver fibrosis. The aim of this study was to define the functional role of cell‐specific adhesion molecule JAM‐A during hepatic fibrogenesis. Methods Complete, conditional (intestinal epithelial; endothelial) and bone marrow chimeric Jam‐a knockout animals and corresponding C57Bl/6 wild‐type animals were treated with carbon tetrachloride (CCl4, 6 weeks). For functional analyses of JAM‐A, comprehensive in vivo studies, co‐culture models and flow‐based adhesion assays were performed. Results Complete and bone marrow‐derived Jam‐a−/− animals showed aggravated fibrosis with increased non‐sinusoidal, perivascular accumulation of CD11b+F4/80+ monocyte‐derived macrophages in contrast to wild‐type mice. Despite being associated with disturbed epithelial barrier function, an intestinal epithelial Jam‐a knockout did not affect fibrogenesis. In endothelial‐specific Jam‐a−/− animals, liver fibrosis was aggravated alongside sinusoid capillarization and hepatic stellate cell (HSC) activation. HSC activation is induced via Jam‐a−/− LSEC‐derived secretion of soluble factors. Sinusoid CD31 expression and hedgehog gene signalling were increased, but leukocyte infiltration and adhesion to LSECs remained unaffected. Conclusions Our models decipher cell‐specific JAM‐A to exert crucial functions during hepatic fibrogenesis. JAM‐A on bone marrow‐derived cells regulates non‐sinusoidal vascular immune cell recruitment, while endothelial JAM‐A controls liver sinusoid capillarization and HSC quiescence.
ISSN:1478-3223
1478-3231
DOI:10.1111/liv.15187