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Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis.
- Source :
-
Gut [Gut] 2017 Mar; Vol. 66 (3), pp. 507-518. Date of Electronic Publication: 2016 Jul 18. - Publication Year :
- 2017
-
Abstract
- Objective: Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.<br />Methods: Experimental liver fibrosis in mice induced by bile duct ligation or CCl <subscript>4</subscript> application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.<br />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.<br />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.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
- Subjects :
- Animals
Carbon Tetrachloride
Listeriosis complications
Listeriosis metabolism
Liver Cirrhosis, Experimental complications
Liver Cirrhosis, Experimental metabolism
Membrane Glycoproteins genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
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
Bacterial Translocation
Immunity, Innate genetics
Interferon Type I metabolism
Interleukin-10 biosynthesis
Listeriosis immunology
Liver Cirrhosis, Experimental immunology
Myeloid Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1468-3288
- Volume :
- 66
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gut
- Publication Type :
- Academic Journal
- Accession number :
- 27432540
- Full Text :
- https://doi.org/10.1136/gutjnl-2015-311224