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

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

Research output: Contribution to journalArticlepeer-review

46 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+CD11bCD11clow 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+CD16high 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

Keywords

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

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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