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IL-22-producing ROR?t-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis.

ABSTRACT: Retinoid-related orphan receptor (ROR) ?t 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 ROR?t-expressing cells in mouse acute hepatitis model using ROR?t deficient (ROR?t(-/-)) mice and RAG-2 and ROR?t double deficient (RAG-2(-/-) × ROR?t(-/-)) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by ROR?t-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 ROR?t(-/-) mice developed liver damage in spite of lack of ROR?t-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2(-/-) × ROR?t(-/-) mice that lacked T and NKT cells. Surprisingly, RAG-2(-/-) × ROR?t(-/-) 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 ROR?t-dependent ILCs play a part of protective roles in hepatic immune response in mice.

SUBMITTER: Matsumoto A

PROVIDER: S-EPMC3633830 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Matsumoto Atsuhiro A Kanai Takanori T Mikami Yohei Y Chu Po-Sung PS Nakamoto Nobuhiro N Ebinuma Hirotoshi H Saito Hidetsugu H Sato Toshiro T Yagita Hideo H Hibi Toshifumi T

PloS one 20130423 4

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 (CC ...[more]

PMID: 23626860

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Project description:BACKGROUND:IL-17 plays a pathogenic role in asthma. ST2- inflammatory group 2 innate lymphoid cells (ILC2s) driven by IL-25 can produce IL-17, whereas ST2+ natural ILC2s produce little IL-17. OBJECTIVE:We characterized ST2+IL-17+ ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2+IL-17+ ILC2s. METHODS:Lung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1-/-, Rorcgfp/gfp, and aryl hydrocarbon receptor (Ahr)-/- mice was examined by using flow cytometry. Bone marrow transfer experiments were performed to evaluate hematopoietic myeloid differentiation primary response gene-88 (MyD88) signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naive ILC2s treated with IL-33, leukotrienes, and inhibitors for nuclear factor of activated T cells, p38, c-Jun N-terminal kinase, or nuclear factor ? light-chain enhancer of activated B cells. The pathogenesis of IL-17+ ILC2s was determined by transferring wild-type or Il17-/- ILC2s to Rag2-/-Il2rg-/- mice, which further induced lung inflammation. Finally, expression of 106 ILC2 signature genes was compared between ST2+IL-17+ ILC2s and ST2+IL-17- ILC2s. RESULTS:Papain or IL-33 treatment boosted IL-17 production from ST2+ ILC2s (referred to by us as ILC217s) but not ST2- ILC2s. Ahr, but not retinoic acid receptor-related orphan receptor ?t, facilitated the production of IL-17 by ILC217s. The hematopoietic compartment of MyD88 signaling is essential for ILC217 induction. IL-33 works in synergy with leukotrienes, which signal through nuclear factor of activated T-cell activation to promote IL-17 in ILC217s. Il17-/- ILC2s were less pathogenic in lung inflammation. ILC217s concomitantly expressed IL-5 and IL-13 but expressed little GM-CSF. CONCLUSION:During lung inflammation, IL-33 and leukotrienes synergistically induce ILC217s. ILC217s are a highly pathogenic and unexpected source for IL-17 in lung inflammation.

Dataset Information

IL-22-producing ROR?t-dependent innate lymphoid cells play a novel protective role in murine acute hepatitis.

Publications

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

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