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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1185-1203
Number of pages	19
Journal	Liver International
Volume	42
Issue number	5
Early online date	11 Mar 2022
DOIs	https://doi.org/10.1111/liv.15187
Publication status	Published - May 2022

Keywords

EXPRESSION
HSC activation
IMMUNOGLOBULIN SUPERFAMILY
JUNCTIONAL ADHESION MOLECULE
LEUKOCYTE ADHESION
LIVER FIBROSIS
MIGRATION
PLATELETS
PROTEINS
SELECTINS
SINUSOIDAL ENDOTHELIAL-CELLS
cell migration
endothelial cells
junctional adhesion molecules
liver fibrosis
sinusoidal capillarization

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10.1111/liv.15187Licence: CC BY-NC

Cite this

Brozat, J. F., Brandt, E. F., Stark, M., Fischer, P., Wirtz, T. H., Flaßhove, A., Rodenhausen, A. N., Vajen, T., Heinzmann, A. C. A., Schmitz, S. M.-T., Abu Jhaisha, S., Röth, A. A., Koenen, R. R., Sahin, H., Trautwein, C., & Berres, M.-L. (2022). JAM-A is a multifaceted regulator in hepatic fibrogenesis, supporting LSEC integrity and stellate cell quiescence. Liver International, 42(5), 1185-1203. https://doi.org/10.1111/liv.15187

@article{612a56328b434d0d9609ba0a2f428f92,

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

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 = "EXPRESSION, HSC activation, IMMUNOGLOBULIN SUPERFAMILY, JUNCTIONAL ADHESION MOLECULE, LEUKOCYTE ADHESION, LIVER FIBROSIS, MIGRATION, PLATELETS, PROTEINS, SELECTINS, SINUSOIDAL ENDOTHELIAL-CELLS, cell migration, endothelial cells, junctional adhesion molecules, liver fibrosis, sinusoidal capillarization",

author = "Brozat, {Jonathan F} and Brandt, {Elisa F} and Myriam Stark and Petra Fischer and Wirtz, {Theresa H} and Alexander Fla{\ss}hove and Rodenhausen, {Aaron N} and Tanja Vajen and Heinzmann, {Alexandra C A} and Schmitz, {Sophia M-T} and {Abu Jhaisha}, Samira and R{\"o}th, {Anjali A} and Koenen, {Rory R} and Hacer Sahin and Christian Trautwein and Marie-Luise Berres",

note = "{\textcopyright} 2022 The Authors. Liver International published by John Wiley & Sons Ltd.",

year = "2022",

month = may,

doi = "10.1111/liv.15187",

language = "English",

volume = "42",

pages = "1185--1203",

journal = "Liver International",

issn = "1478-3223",

publisher = "Wiley",

number = "5",

}

Brozat, JF, Brandt, EF, Stark, M, Fischer, P, Wirtz, TH, Flaßhove, A, Rodenhausen, AN, Vajen, T, Heinzmann, ACA, Schmitz, SM-T, Abu Jhaisha, S, Röth, AA, Koenen, RR, Sahin, H, Trautwein, C & Berres, M-L 2022, 'JAM-A is a multifaceted regulator in hepatic fibrogenesis, supporting LSEC integrity and stellate cell quiescence', Liver International, vol. 42, no. 5, pp. 1185-1203. https://doi.org/10.1111/liv.15187

TY - JOUR

T1 - JAM-A is a multifaceted regulator in hepatic fibrogenesis, supporting LSEC integrity and stellate cell quiescence

AU - Brozat, Jonathan F

AU - Brandt, Elisa F

AU - Stark, Myriam

AU - Fischer, Petra

AU - Wirtz, Theresa H

AU - Flaßhove, Alexander

AU - Rodenhausen, Aaron N

AU - Vajen, Tanja

AU - Heinzmann, Alexandra C A

AU - Schmitz, Sophia M-T

AU - Abu Jhaisha, Samira

AU - Röth, Anjali A

AU - Koenen, Rory R

AU - Sahin, Hacer

AU - Trautwein, Christian

AU - Berres, Marie-Luise

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

KW - EXPRESSION

KW - HSC activation

KW - IMMUNOGLOBULIN SUPERFAMILY

KW - JUNCTIONAL ADHESION MOLECULE

KW - LEUKOCYTE ADHESION

KW - LIVER FIBROSIS

KW - MIGRATION

KW - PLATELETS

KW - PROTEINS

KW - SELECTINS

KW - SINUSOIDAL ENDOTHELIAL-CELLS

KW - cell migration

KW - endothelial cells

KW - junctional adhesion molecules

KW - liver fibrosis

KW - sinusoidal capillarization

U2 - 10.1111/liv.15187

DO - 10.1111/liv.15187

M3 - Article

C2 - 35129269

SN - 1478-3223

VL - 42

SP - 1185

EP - 1203

JO - Liver International

JF - Liver International

IS - 5

ER -