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DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia.

ABSTRACT: Infantile cholestatic disorders arise in the context of progressively developing intrahepatic bile ducts. Biliary atresia (BA), a progressive fibroinflammatory disorder of extra- and intrahepatic bile ducts, is the most common identifiable cause of infantile cholestasis and the leading indication for liver transplantation in children. The etiology of BA is unclear, and although there is some evidence for viral, toxic, and complex genetic causes, the exclusive occurrence of BA during a period of biliary growth and remodeling suggests an importance of developmental factors. Interestingly, interferon-? (IFN-?) signaling is activated in patients and in the frequently utilized rhesus rotavirus mouse model of BA, and is thought to play a key mechanistic role. Here we demonstrate intrahepatic biliary defects and up-regulated hepatic expression of IFN-? pathway genes caused by genetic or pharmacological inhibition of DNA methylation in zebrafish larvae. Biliary defects elicited by inhibition of DNA methylation were reversed by treatment with glucocorticoid, suggesting that the activation of inflammatory pathways was critical. DNA methylation was significantly reduced in bile duct cells from BA patients compared to patients with other infantile cholestatic disorders, thereby establishing a possible etiologic link between decreased DNA methylation, activation of IFN-? signaling, and biliary defects in patients.Inhibition of DNA methylation leads to biliary defects and activation of IFN-?-responsive genes, thus sharing features with BA, which we determine to be associated with DNA hypomethylation. We propose epigenetic activation of IFN-? signaling as a common etiologic mechanism of intrahepatic bile duct defects in BA.

SUBMITTER: Matthews RP

PROVIDER: S-EPMC3075951 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia.

Matthews Randolph P RP Eauclaire Steven F SF Mugnier Monica M Lorent Kristin K Cui Shuang S Ross Megan M MM Zhang Zhe Z Russo Pierre P Pack Michael M

Hepatology (Baltimore, Md.) 20110211 3

<h4>Unlabelled</h4>Infantile cholestatic disorders arise in the context of progressively developing intrahepatic bile ducts. Biliary atresia (BA), a progressive fibroinflammatory disorder of extra- and intrahepatic bile ducts, is the most common identifiable cause of infantile cholestasis and the leading indication for liver transplantation in children. The etiology of BA is unclear, and although there is some evidence for viral, toxic, and complex genetic causes, the exclusive occurrence of BA ...[more]

PMID: 21319190

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Project description:Background & aimsBiliary 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.MethodsWe 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.ResultsIL1R1, 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.ConclusionsGenes 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.Lay summaryBiliary atresia is a severe inflammatory and obstructive disease of bile ducts occurring in infancy. Although the cause is unknown, activation of the innate and adaptive immune systems injures the bile duct epithelium. In this study we found that patients' livers had increased expression of inflammasome genes. Using mice engineered to inactivate individual inflammasome genes, the epithelial injury and bile duct obstruction were prevented by the loss of Il1r1 or Nlrp3, with a decreased activation of natural killer cells and expression of cytokines and chemokines. In contrast, the loss of Casp1 did not change the disease phenotype. Combined, the findings point to a differential role of inflammasome gene products in the pathogenic mechanisms of biliary atresia.

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DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia.

Publications

DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia.

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