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Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia.

ABSTRACT: Biliary atresia (BA) is an inflammatory cholangiopathy of infancy. A proposed mechanism regarding the pathogenesis of BA is that of a virus-induced, immune-mediated injury to bile ducts. The rotavirus (RRV)-induced murine model of BA was utilized to determine the hepatic inflammatory response related to ductal obstruction and if the immune response recapitulated human BA. One week after infection, there was a significant increase in liver CD4(+) T cells producing IFN-gamma and in macrophages producing TNF-alpha. The intrahepatic pattern of inflammation evolved rapidly from an initial predominant CD4(+) Th1 cellular response to a subsequent influx of activated macrophages producing TNF-alpha and iNOS. This immune response persisted despite viral clearance and was representative of the hepatic immune profile present in human BA. Utilization of the murine model of BA yielded mechanistic data that can provide much needed insight into the role played by different arms of the immune system related to the pathogenesis of human BA.

SUBMITTER: Mack CL

PROVIDER: S-EPMC1950158 | biostudies-other | 2005 May

REPOSITORIES: biostudies-other

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Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia.

Mack Cara L CL Tucker Rebecca M RM Sokol Ronald J RJ Kotzin Brian L BL

Clinical immunology (Orlando, Fla.) 20050501 2

Biliary atresia (BA) is an inflammatory cholangiopathy of infancy. A proposed mechanism regarding the pathogenesis of BA is that of a virus-induced, immune-mediated injury to bile ducts. The rotavirus (RRV)-induced murine model of BA was utilized to determine the hepatic inflammatory response related to ductal obstruction and if the immune response recapitulated human BA. One week after infection, there was a significant increase in liver CD4(+) T cells producing IFN-gamma and in macrophages pro ...[more]

PMID: 15885644

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Project description: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. LAY SUMMARY:Biliary 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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Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia.

Publications

Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia.

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