Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia

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• 作者：Ashley E. Walther ; Sujit K. Mohanty ; Bryan Donnelly ; Abigail Coots ; Monica McNeal ; Gregory M. Tiao
• 关键词：Biliary atresia ; Rotavirus ; Cholangiocytes ; Myeloid differentiation factor 88 ; Rhesus rotavirus
• 刊名：Journal of Surgical Research
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：184
• 期：1
• 页码：322-329
• 全文大小：1091 K

文摘

Background

Biliary atresia (BA) is a unique neonatal disease resulting from inflammatory and fibrosing obstruction of the extrahepatic biliary tree. Previous studies have demonstrated the critical role of innate immunity and the Th1 response to activated inflammatory cells and overexpressed cytokines in the pathogenesis of BA. Myeloid differentiation factor 88 (MyD88) is a critical adaptor molecule that has been shown to play a crucial role in immunity. We investigated the role of MyD88 in the inflammatory response and development of cholangiopathy in murine BA.

Methods

MyD88 knockout (MyD88^?/?) and wild-type (WT) BALB/c pups were injected with Rhesus rotavirus or saline on day 1 of life. The mice were monitored for clinical symptoms of BA, including jaundice, acholic stools, bilirubinuria, and death. The liver and extrahepatic bile ducts were harvested for histologic evaluation and the quantification of viral content, determination of cytokine expression, and detection of inflammatory cells.

Results

Rhesus rotavirus infection produced symptoms in 100 % of both MyD88^?/? and WT pups, with survival of 18 % of WT and 0 % of MyD88^?/? mice. Histologic analysis demonstrated bile duct obstruction in both MyD88^?/? and WT mice. Viral titers obtained 7?d after infection and expression of interferon-¦Ã and tumor necrosis factor-¦Á at day 3, 5, 8, and 12?after infection revealed no significant differences between the WT and MyD88^?/? mice. Flow cytometry demonstrated similar levels of activated CD8+ T cells and natural killer?cells.

Conclusions

The pathogenesis of murine BA is independent of the MyD88 signaling inflammatory pathway, suggesting alternative mechanisms are crucial in the induction of the model.