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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Keywords

  • Journal Article

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