Regulation of epithelial injury and bile duct obstruction by NLRP3, IL-1R1 in experimental biliary atresia
Author(s): ,
Jorge A. Bezerra
Affiliations:
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, Cincinnati, OH 45229, USA
Corresponding author. Address: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3030, USA. Tel.: +1 513 636 3008; fax: +1 513 636 5581.
,
Sridevi Gutta
Affiliations:
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, Cincinnati, OH 45229, USA
,
Zhenhua Luo
Affiliations:
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, Cincinnati, OH 45229, USA
,
Reena Mourya
Affiliations:
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, Cincinnati, OH 45229, USA
,
Pranavkumar Shivakumar
Affiliations:
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center and the Department of Pediatrics, Cincinnati, OH 45229, USA
,
Tatsuki Mizuochi
Affiliations:
Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-Machi, Kurume 830-0011, Japan
Li Yang
Affiliations:
Division of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
EASL LiverTree™. Bezerra J. Nov 1, 2018; 234547
Dr. Jorge Bezerra
Dr. Jorge Bezerra

Access to this content is an EASL members and LiverTree™ Privileged Users benefit.

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Graphical abstract

Graphical abstract

Genetic depletion of Il1r1 or Nlrp3 significantly suppressed obstruction of bile ducts and epithelial injury. Suppressing dendritic cell activation of NK cells protected against the biliary atresia phenotype. Loss of Casp1 did not improve phenotype, suggesting the epithelial injury independent of canonical signaling.

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.

Keyword(s)
Cholestasis, Liver, Immunity, Inflammasome
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