Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation

PLoS One. 2014 Jan 2;9(1):e84619. doi: 10.1371/journal.pone.0084619. eCollection 2014.

Abstract

The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2(-/-) mice adoptively transferred with CD4(+)CD45RB(high) T cells; and IL-10(-/-) mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b(-)CD11c(low)PDCA-1(+) plasmacytoid dendritic cells (DCs) abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice in parallel with the emergence of macrophages (Mφs) and conventional DCs (cDCs). Furthermore, liver Mφ/cDCs emerging during intestinal inflammation not only promote the proliferation of naïve CD4(+) T cells, but also instruct them to differentiate into IFN-γ-producing Th1 cells in vitro. The emergence of pathological Mφ/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS)-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mφ/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / pathology
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / pathology
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Disease Models, Animal
  • Hepatitis / etiology*
  • Hepatitis / pathology*
  • Inflammatory Bowel Diseases / complications*
  • Inflammatory Bowel Diseases / immunology*
  • Liver / immunology
  • Liver / pathology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Th1 Cells / immunology
  • Th1 Cells / pathology

Grants and funding

This study was supported in part by Grants-in-Aid for Scientific Research [21390233], Scientific Research on Priority Areas [22021038] from the Japanese Ministry of Education, Culture, Sports, Science and Technology; a Grant-in-Aid for Young Scientists [22790667] from the Japanese Ministry of Health, Labour and Welfare; Health and Labour Sciences Research Grants for research on intractable diseases from the Japanese MIKAMI ET AL Ministry of Health, Labour and Welfare; a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.