title: IL-22-producing RORγt-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis.
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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mikami
authors.forename: Po-Sung
authors.initials: PS
authors.lastname: Chu
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Saito
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D007113:Immunity, Innate; D007378:Interleukins / Q000096:biosynthesis*; D007518:Isoantibodies / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008212:Lymphocyte Depletion; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics*; D000097043:Interleukin-22
chemical_list: D004268:DNA-Binding Proteins; D007378:Interleukins; D007518:Isoantibodies; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22; C064655:V(D)J recombination activating protein 2; C035678:anti-Thy antibody