期刊
GASTROENTEROLOGY
卷 142, 期 2, 页码 366-376出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2011.10.039
关键词
Immune Regulation; Hepatic Disease; Chemokine Receptor; T-Cell Activation
资金
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Japanese Ministry of Health, Labour and Welfare
- Japan Medical Association
- Foundation for Advancement of International Science
- Keio University
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.
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