B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury

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Abstract

Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation-related cancer mortality. Despite most HCC arise from persistent inflammatory conditions; pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2-/- mouse, a model of inflammation-associated cancer, in which ablation of adaptive immunity has been induced genetically (Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice) or with in vivo treatments using lymphocyte-specific depleting antibodies (anti-CD20 or anti-CD4/CD8). We found that activated B and T lymphocytes, secreting fibrogenic TNFα and other pro-inflammatory cytokines, infiltrated the liver of the Mdr2-/- mice, during chronic fibrosing cholangitis. Lymphocytes ablation, in the Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSCs transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic/oxidative state, resulting in skewed macrophages polarization towards an anti-inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the Rag2-/-Mdr2-/- mice, correlating with reduced TNFα-NF-κB pathway activation. Ablation of CD20+ B cells but not of CD4+/CD8+ T cells in the Mdr2-/- mice, promoted senescence-mediated fibrosis resolution and inhibited the pro-tumorigenic TNFα-NF-kB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease free survival in human HCC.

CONCLUSION: Adaptive immunity sustains liver fibrosis and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed to B cell targeting may be an effective strategy in liver fibrosis. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalHepatology
DOIs
Publication statusE-pub ahead of print - Nov 3 2017

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Fibrosis
B-Lymphocytes
Hepatocellular Carcinoma
Liver
Wounds and Injuries
Adaptive Immunity
Inflammation
Hepatic Stellate Cells
Cell Aging
Lymphocytes
Neoplasms
Liver Cirrhosis
T-Lymphocytes
Cholangitis
NF-kappa B
Disease-Free Survival
Extracellular Matrix
Anti-Idiotypic Antibodies
Anti-Inflammatory Agents
Macrophages

Keywords

  • Journal Article

Cite this

@article{0c9e76b7ffd8460480841cb7ecaf8027,
title = "B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury",
abstract = "Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation-related cancer mortality. Despite most HCC arise from persistent inflammatory conditions; pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2-/- mouse, a model of inflammation-associated cancer, in which ablation of adaptive immunity has been induced genetically (Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice) or with in vivo treatments using lymphocyte-specific depleting antibodies (anti-CD20 or anti-CD4/CD8). We found that activated B and T lymphocytes, secreting fibrogenic TNFα and other pro-inflammatory cytokines, infiltrated the liver of the Mdr2-/- mice, during chronic fibrosing cholangitis. Lymphocytes ablation, in the Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSCs transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic/oxidative state, resulting in skewed macrophages polarization towards an anti-inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the Rag2-/-Mdr2-/- mice, correlating with reduced TNFα-NF-κB pathway activation. Ablation of CD20+ B cells but not of CD4+/CD8+ T cells in the Mdr2-/- mice, promoted senescence-mediated fibrosis resolution and inhibited the pro-tumorigenic TNFα-NF-kB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease free survival in human HCC.CONCLUSION: Adaptive immunity sustains liver fibrosis and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed to B cell targeting may be an effective strategy in liver fibrosis. This article is protected by copyright. All rights reserved.",
keywords = "Journal Article",
author = "Francesca Faggioli and Eleonora Palagano and {Di Tommaso}, Luca and Matteo Donadon and Veronica Marrella and Camilla Recordati and Stefano Mantero and Anna Villa and Paolo Vezzoni and Barbara Cassani",
note = "{\circledC} 2017 by the American Association for the Study of Liver Diseases.",
year = "2017",
month = "11",
day = "3",
doi = "10.1002/hep.29636",
language = "English",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury

AU - Faggioli, Francesca

AU - Palagano, Eleonora

AU - Di Tommaso, Luca

AU - Donadon, Matteo

AU - Marrella, Veronica

AU - Recordati, Camilla

AU - Mantero, Stefano

AU - Villa, Anna

AU - Vezzoni, Paolo

AU - Cassani, Barbara

N1 - © 2017 by the American Association for the Study of Liver Diseases.

PY - 2017/11/3

Y1 - 2017/11/3

N2 - Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation-related cancer mortality. Despite most HCC arise from persistent inflammatory conditions; pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2-/- mouse, a model of inflammation-associated cancer, in which ablation of adaptive immunity has been induced genetically (Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice) or with in vivo treatments using lymphocyte-specific depleting antibodies (anti-CD20 or anti-CD4/CD8). We found that activated B and T lymphocytes, secreting fibrogenic TNFα and other pro-inflammatory cytokines, infiltrated the liver of the Mdr2-/- mice, during chronic fibrosing cholangitis. Lymphocytes ablation, in the Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSCs transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic/oxidative state, resulting in skewed macrophages polarization towards an anti-inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the Rag2-/-Mdr2-/- mice, correlating with reduced TNFα-NF-κB pathway activation. Ablation of CD20+ B cells but not of CD4+/CD8+ T cells in the Mdr2-/- mice, promoted senescence-mediated fibrosis resolution and inhibited the pro-tumorigenic TNFα-NF-kB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease free survival in human HCC.CONCLUSION: Adaptive immunity sustains liver fibrosis and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed to B cell targeting may be an effective strategy in liver fibrosis. This article is protected by copyright. All rights reserved.

AB - Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation-related cancer mortality. Despite most HCC arise from persistent inflammatory conditions; pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2-/- mouse, a model of inflammation-associated cancer, in which ablation of adaptive immunity has been induced genetically (Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice) or with in vivo treatments using lymphocyte-specific depleting antibodies (anti-CD20 or anti-CD4/CD8). We found that activated B and T lymphocytes, secreting fibrogenic TNFα and other pro-inflammatory cytokines, infiltrated the liver of the Mdr2-/- mice, during chronic fibrosing cholangitis. Lymphocytes ablation, in the Rag2-/-Mdr2-/- and μMt-Mdr2-/- mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSCs transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic/oxidative state, resulting in skewed macrophages polarization towards an anti-inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the Rag2-/-Mdr2-/- mice, correlating with reduced TNFα-NF-κB pathway activation. Ablation of CD20+ B cells but not of CD4+/CD8+ T cells in the Mdr2-/- mice, promoted senescence-mediated fibrosis resolution and inhibited the pro-tumorigenic TNFα-NF-kB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease free survival in human HCC.CONCLUSION: Adaptive immunity sustains liver fibrosis and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed to B cell targeting may be an effective strategy in liver fibrosis. This article is protected by copyright. All rights reserved.

KW - Journal Article

U2 - 10.1002/hep.29636

DO - 10.1002/hep.29636

M3 - Article

JO - Hepatology

JF - Hepatology

SN - 0270-9139

ER -