CCR9+ Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis
CCR9+ Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis
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DOI：
10.1053/j.gastro.2011.10.039
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发表时间：
2012-02-01
期刊：
影响因子：
29.4
通讯作者：
Hibi, Toshifumi
中科院分区：
文献类型：
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作者：
Nakamoto, Nobuhiro;Ebinuma, Hirotoshi;Hibi, Toshifumi
背景与目的：抗原提呈细胞参与了肝脏炎症的诱导。我们研究了特异性APC在小鼠急性肝损伤发病机制中的作用。方法：用刀豆蛋白A(ConA)或四氯化碳诱导小鼠急性肝脏炎症，研究表达CCR9的巨噬细胞的作用。结果：注射conA后，小鼠肝脏中表达肿瘤坏死因子-α的CCR9(+)CD11b(+)CD11c(-)巨噬细胞消失，而在正常肝脏中大量存在的CCR9(+)Siglec-H(+)CD11b(-)CD11c(低)浆细胞样树突状细胞(PDC)消失。在缺乏淋巴细胞和自然杀伤T细胞的RAG-2(-/-)小鼠的肝脏中也检测到CCR9(+)巨噬细胞。在炎症条件下，CCR9(+)巨噬细胞在体内和体外诱导幼稚的CD4(+)T细胞成为产生干扰素的Th1细胞。注射conA的CCR9(/)小鼠除非同时接受接受conA的小鼠的CCR9(+)巨噬细胞，否则它们不会发生肝炎；与从注射conA的小鼠分离的CCR9(+)pDC、CCR9(-)pDC或CCR9(-)巨噬细胞相比，CCR9(+)巨噬细胞在其炎症的肝脏中积累更多的CCR9(+)巨噬细胞；注射conA后肝脏中CCL25信使RNA的水平增加；针对CCL25的中和抗体通过阻断CCR9(+)巨噬细胞的迁移及其产生的肿瘤坏死因子-α而减少ConA诱导的肝炎。急性肝炎患者外周血中产生肿瘤坏死因子-α的CCR9(+)、CD14(+)、CD16(高)单核细胞数量明显多于对照组。结论：CCR9(+)巨噬细胞参与了急性肝炎模型小鼠肝脏炎症的诱导。
BACKGROUND & AIMS: Antigen-presenting cells (APCs) are involved in the induction of liver inflammation. We investigated the roles of specific APCs in the pathogenesis of acute liver injury in mice. METHODS: We used concanavalin A (con A) or carbon tetrachloride to induce acute liver inflammation in mice and studied the roles of macrophages that express CCR9. RESULTS: After injection of con A, we detected CCR9(+)CD11b(+)CD11c(-)macrophages that express tumor necrosis factor (TNF)-alpha in livers of mice, whereas CCR9(+) Siglec-H(+)CD11b(-)CD11c(low) plasmacytoid DCs (pDCs), which are abundant in normal livers, disappeared. The CCR9(+) macrophages were also detected in the livers of RAG-2(-/-) mice, which lack lymphocytes and natural killer T cells, after injection of con A. Under inflammatory conditions, CCR9(+) macrophages induced naive CD4(+) T cells to become interferon gamma-producing Th1 cells in vivo and in vitro. CCR9 (/) mice injected with con A did not develop hepatitis unless they also received CCR9(+) macrophages from mice that received con A; more CCR9(+) macrophages accumulated in their inflamed livers than CCR9(+) pDCs, CCR9(-)pDCs, or CCR9(-)macrophages isolated from mice that had received injections of con A. Levels of CCL25 messenger RNA increased in livers after injection of con A; neutralizing antibodies against CCL25 reduced the induction of hepatitis by con A by blocking the migration of CCR9(+) macrophages and their production of TNF-alpha. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-alpha-producing CCR9(+)CD14(+) CD16(high) monocytes than controls. CONCLUSIONS: CCR9(+)macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.