Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia.
Role of myeloid differentiation factor 88 in Rhesus rotavirus-induced biliary atresia.
复制标题
骨髓分化因子 88 在恒河猴轮状病毒诱导的胆道闭锁中的作用。
DOI：
10.1016/j.jss.2013.05.032
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Tiao,GregoryM
中科院分区：
文献类型：
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作者：
Walther,AshleyE;Mohanty,SujitK;Donnelly,Bryan;Coots,Abigail;McNeal,Monica;Tiao,GregoryM
胆道闭锁（BA）是一种独特的新生儿疾病，由于肝外胆道系统的炎症和纤维化阻塞而引起。以往的研究表明，先天免疫和Th 1对活化的炎性细胞和过表达的细胞因子的反应在BA的发病机制中起着至关重要的作用。髓样分化因子88（MyD 88）是一种重要的衔接分子，已被证明在免疫中起着至关重要的作用。我们研究了MyD 88在小鼠BA.MethodsMyD88基因敲除（MyD 88 −/−）和野生型（WT）BALB/c幼鼠的炎症反应和胆管病变的发展中的作用。监测小鼠的BA临床症状，包括黄疸、无胆便、胆红素尿和死亡。收获的肝脏和肝外胆管进行组织学评价和病毒含量的定量，细胞因子表达的测定，并检测炎症cells.ResultsRhesus轮状病毒感染产生的症状在100%的MyD 88 −/−和WT幼崽，与生存的18%的WT和0%的MyD 88 −/−小鼠。组织学分析显示MyD 88 −/−和WT小鼠的胆管阻塞。感染后7天获得的病毒滴度以及感染后第3、5、8和12天干扰素-γ和肿瘤坏死因子-α的表达显示WT和MyD 88 −/−小鼠之间没有显著差异。流式细胞仪显示类似水平的活化的CD 8 + T细胞和自然杀伤cells.ConclusionsThe发病机制的小鼠BA是独立的MyD 88信号炎症通路，这表明替代机制是至关重要的诱导模型。
BackgroundBiliary 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.MethodsMyD88 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.ResultsRhesus 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-γ and tumor necrosis factor-α 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.ConclusionsThe pathogenesis of murine BA is independent of the MyD88 signaling inflammatory pathway, suggesting alternative mechanisms are crucial in the induction of the model.