Rag2-deficient IL-1 Receptor Antagonist-deficient Mice Are a Novel Colitis Model in Which Innate Lymphoid Cell-derived IL-17 Is Involved in the Pathogenesis

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Author(s)

    • AKITSU Aoi Akitsu Aoi
    • Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan| Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan| Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan
    • KAKUTA Shigeru Kakuta Shigeru
    • Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan| Present address: Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
    • SAIJO Shinobu [他] Saijo Shinobu
    • Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan| Present address: Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 263-8522, Japan
    • Iwakura Yoichiro
    • Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan| Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan| Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-0022, Japan

Abstract

<i>Il1rn</i><sup>−/−</sup> mice spontaneously develop arthritis and aortitis by an autoimmune mechanism and also develop dermatitis by an autoinflammatory mechanism. Here, we show that <i>Rag2</i><sup>−/−</sup><i>Il1rn</i><sup>−/−</sup> mice develop spontaneous colitis with high mortality, making a contrast to the suppression of arthritis in these mice. Enhanced IL-17A expression in group 3 innate lymphoid cells (ILC3s) was observed in the colon of <i>Rag2</i><sup>−/−</sup><i>Il1rn</i><sup>−/−</sup> mice. IL-17A-deficiency prolonged the survival of <i>Rag2</i><sup>−/−</sup><i>Il1rn</i><sup>−/−</sup> mice, suggesting a pathogenic role of this cytokine in the development of intestinal inflammation. Although IL-17A-producing T cells were increased in <i>Il1rn</i><sup>−/−</sup> mice, these mice did not develop colitis, because CD4<sup>+</sup>Foxp3<sup>+</sup> regulatory T cell population was also expanded. Thus, excess IL-1 signaling and IL-1-induced IL-17A from ILC3s cause colitis in <i>Rag2<sup>−/−</sup>Il1rn<sup>−/−</sup></i> mice in which Treg cells are absent. These observations suggest that the balance between IL-17A-producing cells and Treg cells is important to keep the immune homeostasis of the colon.

Journal

  • Experimental Animals

    Experimental Animals 63(2), 235-246, 2014

    Japanese Association for Laboratory Animal Science

Codes

  • NII Article ID (NAID)
    130003391627
  • NII NACSIS-CAT ID (NCID)
    AA11032321
  • Text Lang
    ENG
  • ISSN
    1341-1357
  • NDL Article ID
    025412061
  • NDL Call No.
    Z54-H752
  • Data Source
    NDL  J-STAGE 
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