MicroRNA-223 Acts as an Important Regulator to Kupffer Cells Activation at the Early Stage of Con A-Induced Acute Liver Failure via AIM2 Signaling Pathway
MicroRNA-223 Acts as an Important Regulator to Kupffer Cells Activation at the Early Stage of Con A-Induced Acute Liver Failure via AIM2 Signaling Pathway
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DOI：
10.1159/000369658
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发表时间：
2014-12
影响因子：
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通讯作者：
Fan Yang;G. Lou;Xiaotang Zhou;Min Zheng;Ji-liang He;Zhi Chen
中科院分区：
文献类型：
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作者：
Fan Yang;G. Lou;Xiaotang Zhou;Min Zheng;Ji-liang He;Zhi Chen
背景：急性肝功能衰竭(ALF)是一种快速、严重的临床综合征，可导致多器官功能障碍和衰竭。在ALF的发病过程中，Kupffer细胞的早期激活参与了一些强烈的炎症反应。然而，Kupffer细胞在ALF过程中激活的详细调控机制仍不清楚。本研究旨在发现急性肾功能衰竭早期Kupffer细胞激活的潜在调控因素，并对其进行更深入的研究。方法：采用刀豆蛋白A注射建立小鼠ALF模型。通过对典型细胞因子的检测，显示了ALF早期Kupffer细胞的动态免疫状态。从RNA和蛋白质水平检测炎性小体AIM2的表达。体外核糖核酸干扰实验证实其通过诱导IL-1β的产生而影响枯否细胞的活化。此外，通过Q-PCR检测miR-223在体内的表达，并通过RNA转染法检测miR-223在ConA诱导的ALF过程中对Kupffer细胞活化的调节作用。结果：分离培养的Kupffer细胞大量产生IL-1β可能是急性肾衰过程中Kupffer细胞促炎活化的主要驱动力。AIM2通过诱导IL-1β的产生而影响枯否细胞的促炎活性，在ALF中起着至关重要的作用。进一步研究发现，miR-223通过AIM2途径影响IL-1β的产生，在急性肾衰早期对枯否细胞的激活起调节作用。结论：首次证实miR223通过AIM2途径抑制IL-1β的产生，从而抑制急性肾衰早期枯否细胞的促炎活性。因此，它在ALF的发病机制中起着重要作用。
Background: Acute liver failure (ALF), known as a rapid and severe clinical syndrome, can induce multiple organ dysfunction and failure. It was noticed that Kupffer cells activation at the initial phase was involved in some intense inflammatory responses in the pathogenesis of ALF. However, detailed regulation mechanism of Kupffer cells activation during ALF is still obscured. Present study aimed to discover the potential regulator and explore deeper information of Kupffer cells activation at the early stage of ALF. Methods: The mouse model of ALF was established by Concanavalin A injection. Dynamic immunological statuses of Kupffer cells at the early stage of ALF were exhibited by detecting typical cytokines. The expression of inflammasome AIM2 was measured in both RNA and protein level. Its role of affecting Kupffer cells activation during ALF by inducing IL-1β production was identified by RNA interference in vitro. Moreover, the expression of miR-223 in vivo was measured by q-PCR and its role in regulating Kupffer cells activation during Con A induced ALF was determined by RNAs transfection. Results: Present study showed that mass production of IL-1β from isolated Kupffer cells in Con A treated mice might be the main driving force of Kupffer cells pro-inflammatory activation during ALF. The role of AIM2 in affecting pro-inflammatory activation of Kupffer cells by inducing IL-1β production was crucial to ALF. Further study found that miR-223 acted as a regulator in Kupffer cells activation at the early stage of ALF by influencing IL-1β production via AIM2 pathway. Conclusion: For the first time, this paper demonstrated that miR-223 acted to inhibit IL-1β production via AIM2 pathway, suppressing Kupffer cells pro-inflammatory activation at the early stage of ALF. Thus, it played an important role in the pathogenesis of ALF.