Journal
JOURNAL OF HEPATOLOGY
Volume 69, Issue 5, Pages 1136-1144Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2018.05.038
Keywords
Cholestasis; Liver; Immunity; Inflammasome
Categories
Funding
- NIH [DK-64008, DK-83781]
- Integrative Morphology of the Digestive Health Center [DK-78392]
- Gene Analysis Cores of the Digestive Health Center [DK-78392]
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK078392, R01DK083781, R01DK064008] Funding Source: NIH RePORTER
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Background & Aims: Biliary atresia (BA) results from a neonatal inflammatory and fibrosing obstruction of bile ducts of unknown etiology. Although the innate immune system has been linked to the virally induced mechanism of disease, the role of inflammasome-mediated epithelial injury remains largely undefined. Here, we hypothesized that disruption of the inflammasome suppresses the neonatal proinflammatory response and prevents experimental BA. Methods: We determined the expression of key inflammasome-related genes in livers from infants at diagnosis of BA and in extrahepatic bile ducts (EHBDs) of neonatal mice after infection with rotavirus (RRV) immediately after birth. Then, we determined the impact of the wholesale inactivation of the genes encoding IL-1R1 (Il1r1(-/-)), NLRP3 (Nlrp3(-/-)) or caspase-1 (Casp1(-/-)) on epithelial injury and bile duct obstruction. Results: IL1R1, NLRP3 and CASP1 mRNA increased significantly in human livers at the time of diagnosis, and in EHBDs of RRV-infected mice. In Il1r1(-/-) mice, the epithelial injury of EHBDs induced by RRV was suppressed, with dendritic cells unable to activate natural killer cells. A similar protection was observed in Nlrp3(-/-) mice, with decreased injury and inflammation of livers and EHBDs. Long-term survival was also improved. In contrast, the inactivation of the Casp1 gene had no impact on tissue injury, and all mice died. Tissue analyses in Il1r1(-/-) and Nlrp3(-/-) mice showed decreased populations of dendritic cells and natural killer cells and suppressed expression of type-1 cytokines and chemokines. Conclusions: Genes of the inflammasome are overexpressed at diagnosis of BA in humans and in the BA mouse model. In the experimental model, the targeted loss of IL-1R1 or NLRP3, but not of caspase-1, protected neonatal mice against RRV-induced bile duct obstruction. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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