Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis

Gut. 2017 Mar;66(3):507-518. doi: 10.1136/gutjnl-2015-311224. Epub 2016 Jul 18.

Abstract

Objective: Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.

Methods: Experimental liver fibrosis in mice induced by bile duct ligation or CCl4 application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.

Results: In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection with Listeria that activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis.

Conclusions: In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.

Keywords: BACTERIAL INFECTION; HEPATIC FIBROSIS; IMMUNE RESPONSE; LIVER CIRRHOSIS; LIVER IMMUNOLOGY.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Translocation*
  • Carbon Tetrachloride
  • Immunity, Innate* / genetics
  • Interferon Type I / metabolism*
  • Interleukin-10 / biosynthesis*
  • Listeriosis / complications
  • Listeriosis / immunology*
  • Listeriosis / metabolism
  • Liver Cirrhosis, Experimental / complications
  • Liver Cirrhosis, Experimental / immunology*
  • Liver Cirrhosis, Experimental / metabolism
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Myeloid Cells / microbiology
  • Myxovirus Resistance Proteins / genetics
  • Receptor, Interferon alpha-beta / antagonists & inhibitors
  • Receptor, Interferon alpha-beta / genetics
  • Receptors, Interleukin-10 / antagonists & inhibitors
  • Receptors, Pattern Recognition / genetics
  • Signal Transduction
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 9 / genetics

Substances

  • Interferon Type I
  • Membrane Glycoproteins
  • Mx1 protein, mouse
  • Myxovirus Resistance Proteins
  • Receptors, Interleukin-10
  • Receptors, Pattern Recognition
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Tlr7 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Interleukin-10
  • Receptor, Interferon alpha-beta
  • Carbon Tetrachloride