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

Nobuhiro Nakamoto, Hirotoshi Ebinuma, Takanori Kanai, Hakusyo Cho, Yuichi Ono, Yohei Mikami, Keisuke Ojiro, Martin Lipp, Paul E. Love, Hidetsugu Saito, Toshifumi Hibi

Research output: Contribution to journalArticle

41 Citations (Scopus)

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)-α in livers of mice, whereas CCR9 +SiglecH +CD11bCD11c 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 gammaproducing 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-αproducing CCR9 +CD14 +CD16 high monocytes than controls. Conclusions: CCR9 + macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

Original languageEnglish
Pages (from-to)366-376
Number of pages11
JournalGastroenterology
Volume142
Issue number2
DOIs
Publication statusPublished - 2012 Feb

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Hepatitis
Macrophages
Concanavalin A
Inflammation
Liver
Injections
Tumor Necrosis Factor-alpha
Antigen-Presenting Cells
Th1 Cells
Natural Killer T-Cells
Carbon Tetrachloride
Neutralizing Antibodies
Interferons
Monocytes
Lymphocytes
T-Lymphocytes
Messenger RNA
Wounds and Injuries

Keywords

  • Chemokine Receptor
  • Hepatic Disease
  • Immune Regulation
  • T-Cell Activation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

CCR9 + macrophages are required for acute liver inflammation in mouse models of hepatitis. / Nakamoto, Nobuhiro; Ebinuma, Hirotoshi; Kanai, Takanori; Cho, Hakusyo; Ono, Yuichi; Mikami, Yohei; Ojiro, Keisuke; Lipp, Martin; Love, Paul E.; Saito, Hidetsugu; Hibi, Toshifumi.

In: Gastroenterology, Vol. 142, No. 2, 02.2012, p. 366-376.

Research output: Contribution to journalArticle

Nakamoto, N, Ebinuma, H, Kanai, T, Cho, H, Ono, Y, Mikami, Y, Ojiro, K, Lipp, M, Love, PE, Saito, H & Hibi, T 2012, 'CCR9 + macrophages are required for acute liver inflammation in mouse models of hepatitis', Gastroenterology, vol. 142, no. 2, pp. 366-376. https://doi.org/10.1053/j.gastro.2011.10.039
Nakamoto, Nobuhiro ; Ebinuma, Hirotoshi ; Kanai, Takanori ; Cho, Hakusyo ; Ono, Yuichi ; Mikami, Yohei ; Ojiro, Keisuke ; Lipp, Martin ; Love, Paul E. ; Saito, Hidetsugu ; Hibi, Toshifumi. / CCR9 + macrophages are required for acute liver inflammation in mouse models of hepatitis. In: Gastroenterology. 2012 ; Vol. 142, No. 2. pp. 366-376.
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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)-α in livers of mice, whereas CCR9 +SiglecH +CD11bCD11c 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 gammaproducing 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-αproducing 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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T1 - CCR9 + macrophages are required for acute liver inflammation in mouse models of hepatitis

AU - Nakamoto, Nobuhiro

AU - Ebinuma, Hirotoshi

AU - Kanai, Takanori

AU - Cho, Hakusyo

AU - Ono, Yuichi

AU - Mikami, Yohei

AU - Ojiro, Keisuke

AU - Lipp, Martin

AU - Love, Paul E.

AU - Saito, Hidetsugu

AU - Hibi, Toshifumi

PY - 2012/2

Y1 - 2012/2

N2 - 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)-α in livers of mice, whereas CCR9 +SiglecH +CD11bCD11c 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 gammaproducing 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-αproducing CCR9 +CD14 +CD16 high monocytes than controls. Conclusions: CCR9 + macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

AB - 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)-α in livers of mice, whereas CCR9 +SiglecH +CD11bCD11c 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 gammaproducing 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-αproducing CCR9 +CD14 +CD16 high monocytes than controls. Conclusions: CCR9 + macrophages contribute to the induction of acute liver inflammation in mouse models of hepatitis.

KW - Chemokine Receptor

KW - Hepatic Disease

KW - Immune Regulation

KW - T-Cell Activation

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