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

Jonathan F Brozat; Elisa F Brandt; Myriam Stark; Petra Fischer; Theresa H Wirtz; Alexander Flaßhove; Aaron N Rodenhausen; Tanja Vajen; Alexandra C A Heinzmann; Sophia M-T Schmitz; Samira Abu Jhaisha; Anjali A Röth; Rory R Koenen; Hacer Sahin; Christian Trautwein; Marie-Luise Berres

doi:10.1111/liv.15187

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

Liver Int. 2022 May;42(5):1185-1203. doi: 10.1111/liv.15187. Epub 2022 Mar 11.

Authors

Jonathan F Brozat¹, Elisa F Brandt¹, Myriam Stark¹, Petra Fischer¹, Theresa H Wirtz¹, Alexander Flaßhove¹, Aaron N Rodenhausen¹, Tanja Vajen², Alexandra C A Heinzmann³, Sophia M-T Schmitz⁴, Samira Abu Jhaisha¹, Anjali A Röth⁴, Rory R Koenen³, Hacer Sahin¹, Christian Trautwein¹, Marie-Luise Berres¹

Affiliations

¹ Department of Internal Medicine III, RWTH Aachen University Hospital, RWTH Aachen, Aachen, Germany.
² Cardiovascular Research Laboratory, Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
³ Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
⁴ Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, RWTH Aachen, Aachen, Germany.

PMID: 35129269
DOI: 10.1111/liv.15187

Abstract

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.

Keywords: HSC activation; cell migration; endothelial cells; junctional adhesion molecules; liver fibrosis; sinusoidal capillarization.

MeSH terms

Animals
Endothelial Cells / metabolism
Fibrosis
Hedgehog Proteins / metabolism
Hepatic Stellate Cells / metabolism
Humans
Junctional Adhesion Molecule A* / metabolism
Liver / pathology
Liver Cirrhosis / pathology
Mice
Mice, Inbred C57BL

Substances

Hedgehog Proteins
Junctional Adhesion Molecule A