Original ResearchBasic and Translational—LiverCCR9+ Macrophages Are Required for Acute Liver Inflammation in Mouse Models of Hepatitis
Section snippets
Experimental Protocols of con A–Induced Hepatitis
Con A (type IV) was purchased from Sigma-Aldrich (St Louis, MO). Intravenous injections of con A (20 mg/kg) were administered into the tail vein of mice 12 hours before examination under anesthesia. In experiment 1, age-matched wild-type (WT), CCR9−/−, CCR7−/−, and MCP-1−/− mice were treated with con A. In experiment 2, CCR9+ and CCR9− macrophages as well as CCR9+ and CCR9− pDCs were isolated from the liver of con A–treated Ly5.1+ mice. These cells were then adoptively transferred to CCR9−/−
Abundant CCR9+CD11b−CD11clow pDCs in the Normal Liver
To clarify the mechanism by which liver inflammation is induced, we focused on liver APCs.1, 2, 15, 16 To segmentalize the APC compartments, we stained liver and spleen mononuclear cells obtained from WT mice with mAb against CD11b and CD11c. As shown in Figure 1A, 3 APC compartments were found in the liver and spleen: cDCs, CD11b+CD11c+; pDCs, CD11b−CD11clow; and macrophages, CD11b+CD11c−. As previously reported,1 pDCs are more abundant in the liver than in the spleen, although the ratios of
Discussion
We here identify CCR9+ macrophages as key inflammatory cells of con A–induced AH in mice. Figure 7F gives a schematic view of the current study. Our results clearly show that CCR9+ macrophages played a key role in promoting proliferation of CD4+ T cells and generation of IFN-γ–producing Th1 cells as well as NKT cell activation in con A–induced T-cell hepatitis.
To investigate the mechanism of the breakdown of liver tolerance in the inflammatory state, we initially focused on resident
Acknowledgments
H.E. and T.K. contributed equally to this work.
The authors thank K. Tsuchimoto (Kitasato Institute Hospital), R. Umeda, and S. Usui (Keio University) for providing human materials and for critical comments, as well as K. Toda (Kitasato Institute Hospital) for technical assistance.
References (30)
- et al.
Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis
Gastroenterology
(2006) - et al.
Role of beta7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease
Gastroenterology
(2008) - et al.
Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12
Blood
(2006) - et al.
Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors
Blood
(2006) - et al.
Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells
J Hepatol
(2008) - et al.
Plasmacytoid dendritic cells mediate oral tolerance
Immunity
(2008) The liver as a lymphoid organ
Annu Rev Immunol
(2009)- et al.
The roles of innate immune cells in liver injury and regeneration
Cell Mol Immunol
(2007) - et al.
Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization
Gastroenterology
(2008) - et al.
Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade
PLoS Pathog
(2009)
Antigen-presenting cell function in the tolerogenic liver environment
Nat Rev Immunol
Etiology and prognosis of fulminant hepatitis in adults
Liver Transpl
Functional role of chemokines in liver disease models
Nat Rev Gastroenterol Hepatol
CCR9 and inflammatory bowel disease
Expert Opin Ther Targets
Phenotype and effector function of CC chemokine receptor 9-expressing lymphocytes in small intestinal Crohn's disease
J Immunol
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Conflicts of interest The authors disclose no conflicts.
Funding Supported part by grants-in-aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research and Creative Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology; the Japanese Ministry of Health, Labour and Welfare; the Japan Medical Association; Foundation for Advancement of International Science; and Keio University Medical Fund.
Writing assistance was provided by Dr Peter Hawkes (Kansai Language College) and Edanz Group Ltd and funded by grants-in-aid for Scientific Research, Scientific Research on Priority Areas, Exploratory Research.