Microbial translocation in liver fibrosis induces chronic IFNAR signaling that directly affects innate immune responses to systemic bacterial infection

Le résumé fourni par la source

A common clinical complication in patients with liver fibrosis or cirrhosis is exacerbations of bacterial infections, which often persist in these patients. In order to study the underlying pathophysiological cellular and molecular mechanisms in mice, we investigated the immune responses to Listeria infections in the context of liver fibrosis. Using the bile-duct ligation model for the induction of liver fibrosis in mice we found an enhanced susceptibility to Listeria infections leading to persistence of infection, recapitulating clinical situations in humans. While the innate clearance of Listeria in the spleen of those mice was unaltered, bactericidal activity of intrahepatic macrophages and bacterial clearance in the liver were strongly impaired. This reduced local clearance of Listeria was correlated to impaired IFNγ, IL-12 and ROS production by the myeloid cells in the liver. Mechanistically, we identified IFNAR signaling in the myeloid cells as the basis for impaired anti-bacterial immune responses in mice with liver fibrosis. Using germ free mice we could show that IFNAR signaling is induced by translocated gut microbiota during liver fibrosis. This chronic Type I IFN signals on myeloid cells in turn lead to IL-10 release, which directly inhibited IFNγ, IL-12 and ROS production. Strikingly, we could rescue mice form chronic infection by either blocking IFN signaling in myeloid cells or systemic blockade of IL10 signaling, opening an exciting new therapeutic avenue for bacterial infections in patients suffering from liver fibrosis or cirrhosis. Corresponding author: Abdullah, Zeinab E-Mail: zeinab.abdullah@ukb.uni-bonn.de

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.