3 years ago

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

Matteo Donadon, Paolo Vezzoni, Anna Villa, Eleonora Palagano, Camilla Recordati, Barbara Cassani, Veronica Marrella, Francesca Faggioli, Luca Di Tommaso, Stefano Mantero
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.

Publisher URL: http://doi.org/10.1002/hep.29636

DOI: 10.1002/hep.29636

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