title: CCR9+ macrophages are required for acute liver inflammation in mouse models of hepatitis.
abstract: OBJECTIVE
  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)-α 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-α. Peripheral blood samples from patients with acute hepatitis had greater numbers of TNF-α-producing CCR9(+)CD14(+)CD16(high) monocytes than controls.
  
  
  CONCLUSIONS
  CCR9(+) macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Po-Sung
authors.initials: PS
authors.lastname: Chu
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ono
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mikami
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ojiro
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Paul E
authors.initials: PE
authors.lastname: Love
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Saito
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism; D003208:Concanavalin A; D004195:Disease Models, Animal; D006505:Hepatitis / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054388:Receptors, CCR / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C119309:CC chemokine receptor 9; D054388:Receptors, CCR; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D002251:Carbon Tetrachloride