Central role of the TIR-domain-containing adaptor-inducing interferon-β (TRIF) adaptor protein in murine sterile liver injury.
Central role of the TIR-domain-containing adaptor-inducing interferon-β (TRIF) adaptor protein in murine sterile liver injury.
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DOI：
10.1002/hep.29078
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Crispe IN
中科院分区：
文献类型：
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作者：
Brempelis KJ;Yuen SY;Schwarz N;Mohar I;Crispe IN
多种途径驱动肝脏的无菌性损伤反应；然而，尚不清楚受损细胞的类型或损伤机制如何激活这些途径。在此，我们使用一种选择性肝细胞死亡模型来研究无菌性肝损伤。在该模型中，含TIR结构域的衔接蛋白诱导干扰素-β（TRIF）是所产生的肝内炎症反应的核心介质，其独立于上游Toll样受体4（TLR4）信号传导和下游I型干扰素信号传导。TRIF是诱导白细胞介素 - 10（IL - 10）、白细胞介素 - 6（IL - 6）和白细胞介素 - 1β（IL - 1β）细胞因子所必需的。相反，尽管在大多数TRIF - / - 小鼠中，趋化因子（Ccl2、Ccl7、Cxcl1、Cxcl2和Cxcl10）和细胞黏附（Icam1和Vcam1）基因（这些基因参与髓样细胞募集）的诱导以及CCL2和CXCL1趋化因子的上调减少，但一部分TRIF - / - 小鼠表现出突破性炎症以及诱导这些基因和蛋白质的能力，这表明存在冗余途径来应对肝细胞死亡。此外，我们发现肝细胞自身是对肝细胞死亡的主要应答细胞，其参与髓样细胞募集的基因转录增加量多于肝窦内皮细胞（LSECs）或枯否细胞（KCs）。
我们的研究确定了一种依赖TRIF、不依赖TLR4和I型干扰素的无菌性肝损伤途径，在该途径中，肝细胞既是损伤的靶细胞，也是主要的应答细胞类型。
Multiple pathways drive the sterile injury response in the liver; however, it is unclear how the type of cells injured or the mechanism of injury activates these pathways. Here, we use a model of selective hepatocyte death to investigate sterile liver injury. In this model, the TIR-domain-containing adaptor-inducing interferon-β (TRIF) was a central mediator of the resulting intrahepatic inflammatory response that was independent of both upstream Toll-like receptor (TLR) 4 signaling and downstream type I IFN signaling. TRIF was required for the induction of IL-10, IL-6, and IL-1β cytokines. Conversely, although the induction of CCL2 and CXCL1 chemokines and the up-regulation of chemokine (Ccl2, Ccl7, Cxcl1, Cxcl2, and Cxcl10) and cell-adhesion (Icam1 and Vcam1) genes involved in myeloid cell recruitment was reduced in a majority of TRIF−/− mice, a subset of TRIF−/− mice showed breakthrough inflammation and the ability to induce these genes and proteins, indicating that redundant pathways exist to respond to hepatocyte death. Furthermore, we found that hepatocytes themselves were the main responders to hepatocyte death, increasing transcription of genes involved in myeloid cell recruitment more than either liver sinusoidal endothelial cells (LSECs) or Kupffer cells (KCs). Our studies define a TRIF-dependent, TLR4- and type I IFN-independent pathway of sterile liver injury in which hepatocytes are both the targets of damage and the principal responding cell type.