IL-22-producing RORγt-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis

Atsuhiro Matsumoto; Takanori Kanai; Yohei Mikami; Po-Sung Chu; Nobuhiro Nakamoto; Hirotoshi Ebinuma; Hidetsugu Saito; Toshiro Sato; Hideo Yagita; Toshifumi Hibi

doi:10.1371/journal.pone.0062853

IL-22-producing RORγt-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis

PLoS One. 2013 Apr 23;8(4):e62853. doi: 10.1371/journal.pone.0062853. Print 2013.

Authors

Atsuhiro Matsumoto¹, Takanori Kanai, Yohei Mikami, Po-Sung Chu, Nobuhiro Nakamoto, Hirotoshi Ebinuma, Hidetsugu Saito, Toshiro Sato, Hideo Yagita, Toshifumi Hibi

Affiliation

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Abstract

Retinoid-related orphan receptor (ROR) γt is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORγt-expressing cells in mouse acute hepatitis model using RORγt deficient (RORγt(-/-)) mice and RAG-2 and RORγt double deficient (RAG-2(-/-) × RORγt(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORγt-expressing cells. We detected RORC expression in three compartments, CD4(+) T cells, NKT cells, and lineage marker-negative SCA-1(+)Thy1(high) ILCs, of the liver of wild type (WT) mice. CCl4-treated RORγt(-/-) mice developed liver damage in spite of lack of RORγt-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) × RORγt(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) × RORγt(-/-) mice developed significantly severer CCl4-induced hepatitis compared with RAG-2(-/-) mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2(-/-) mice with the depletion of liver ILCs. Collectively, hepatic RORγt-dependent ILCs play a part of protective roles in hepatic immune response in mice.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Hepatitis, Animal / chemically induced
Hepatitis, Animal / genetics*
Hepatitis, Animal / immunology*
Immunity, Innate*
Interleukin-22
Interleukins / biosynthesis*
Isoantibodies / administration & dosage
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Liver / immunology
Liver / metabolism
Liver / pathology
Lymphocyte Depletion
Lymphocyte Subsets / immunology
Lymphocyte Subsets / metabolism
Lymphocytes / immunology*
Lymphocytes / metabolism*
Mice
Mice, Knockout
Natural Killer T-Cells / immunology
Natural Killer T-Cells / metabolism
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*

Substances

DNA-Binding Proteins
Interleukins
Isoantibodies
Nuclear Receptor Subfamily 1, Group F, Member 3
V(D)J recombination activating protein 2
anti-Thy antibody

Grants and funding

Grant-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, (http://www.mext.go.jp/); Grant-in-Aid for Young Scientists from the Japanese Ministry of Health (http://www.mhlw.go.jp/) and Keio University Grant-in-Aid for Encouragement of Young Medical Scientists from Keio University (http://www.keio.ac.jp/index-jp.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.