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CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis

Official URL:https://doi.org/10.1053/j.gastro.2011.10.039
PubMed:View item in PubMed
Creators Name:Nakamoto, N. and Ebinuma, H. and Kanai, T. and Chu, P.S. and Ono, Y. and Mikami, Y. and Ojiro, K. and Lipp, M. and Love, P.E. and Saito, H. and Hibi, T.
Journal Title:Gastroenterology
Journal Abbreviation:Gastroenterology
Volume:142
Number:2
Page Range:366-376
Date:February 2012
Keywords:Immune Regulation, Hepatic Disease, Chemokine Receptor, T-Cell Activation, Animals, Mice
Abstract: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.
ISSN:0016-5085
Publisher:Saunders / Elsevier (U.S.A.)
Item Type:Article

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