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

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

Jonathan F Brozat  1 , Elisa F Brandt  1 , Myriam Stark  1 , Petra Fischer  1 , Theresa H Wirtz  1 , Alexander Flaßhove  1 , Aaron N Rodenhausen  1 , Tanja Vajen  2 , Alexandra C A Heinzmann  3 , Sophia M-T Schmitz  4 , Samira Abu Jhaisha  1 , Anjali A Röth  4 , Rory R Koenen  3 , Hacer Sahin  1 , Christian Trautwein  1 , Marie-Luise Berres  1
Affiliations

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

Jonathan F Brozat et al. Liver Int. 2022 May.

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.

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References

REFERENCES

    1. McEver RP. Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res. 2015;107(3):331-339.
    1. Mamdouh Z, Mikhailov A, Muller WA. Transcellular migration of leukocytes is mediated by the endothelial lateral border recycling compartment. J Exp Med. 2009;206(12):2795-2808.
    1. Malergue F, Galland F, Martin F, Mansuelle P, Aurrand-Lions M, Naquet P. A novel immunoglobulin superfamily junctional molecule expressed by antigen presenting cells, endothelial cells and platelets. Mol Immunol. 1998;35(17):1111-1119.
    1. Williams LA, Martin-Padura I, Dejana E, Hogg N, Simmons DL. Identification and characterisation of human junctional adhesion molecule (JAM). Mol Immunol. 1999;36(17):1175-1188.
    1. Martin-Padura I, Lostaglio S, Schneemann M, et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. 1998;142(1):117-127.

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