Mincle Signaling Promotes Con A Hepatitis.
Mincle Signaling Promotes Con A Hepatitis.
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DOI：
10.4049/jimmunol.1600598
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发表时间：
2016-10-01
期刊：
影响因子：
--
通讯作者：
Miller G
中科院分区：
文献类型：
--
作者：
Greco SH;Torres-Hernandez A;Kalabin A;Whiteman C;Rokosh R;Ravirala S;Ochi A;Gutierrez J;Salyana MA;Mani VR;Nagaraj SV;Deutsch M;Seifert L;Daley D;Barilla R;Hundeyin M;Nikifrov Y;Tejada K;Gelb BE;Katz SC;Miller G
伴刀豆球蛋白-A（Con-A）肝炎被认为是T细胞介导的急性肝损伤模型。Mincle是一种C型凝集素受体（C-type lectin receptor，C-Lectin receptor），在对分枝杆菌和真菌的免疫应答中至关重要，但在非病原体介导的炎症的临床前模型中没有明确的作用。由于Mincle可以连接细胞死亡配体SAP 130，我们假设Mincle信号转导驱动Con-A肝炎的肝内炎症和肝损伤。使用C57 BL/6、Mincle−/−和Dectin-1−/−小鼠在鼠Con-A肝炎模型中评估急性肝损伤。使用选择性抑制剂评估C/EBPβ和HIF-1α信号传导的作用。我们发现Mincle在小鼠和人类的肝脏先天性炎症细胞和内皮细胞中高度表达。此外，无菌Mincle配体和Mincle信号传导中间体在Con-A肝炎的小鼠肝脏中增加。最重要的是，Mincle缺失或阻断可预防Con-A肝炎，而Mincle连接则会加重疾病。骨髓嵌合和过继转移实验表明，浸润性骨髓细胞中的Mincle信号传导决定了疾病表型。相反，通过其他CLRs的信号传导不会改变疾病进程。从机制上讲，我们发现Mincle阻断降低了NF-κβ相关的信号中间体C/EBPβ和HIF-1α，这两者在巨噬细胞介导的炎症反应中是必需的。因此，Mincle缺失降低了Con-A肝炎中亚硝酸盐的产生，并且C/EBPβ和HIF 1-α的抑制降低了肝脏疾病的严重程度。我们的工作涉及Con-A肝炎的一种新的先天免疫驱动因素，更广泛地说，表明Mincle在由无菌炎症控制的疾病中的潜在作用。
Concanavalin-A (Con-A) hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor (CLR) that is critical in the immune response to mycobacteria and fungi, but does not have a well-defined role in pre-clinical models of non-pathogen mediated inflammation. Since Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con-A hepatitis. Acute liver injury was assessed in the murine Con-A hepatitis model using C57BL/6, Mincle−/−, and Dectin-1−/− mice. The role of C/EBPβ and HIF-1α signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con-A hepatitis. Most significantly, Mincle deletion or blockade protected against Con-A hepatitis whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other CLRs did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-κβ related signaling intermediates, C/EBPβ and HIF-1α, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con-A hepatitis and inhibition of both C/EBPβ and HIF1-α reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con-A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.
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作者：
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