title: An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.
abstract: House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells.
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics, Keio University School of Medicine, Tokyo, 160-8582, Japan; Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos 7270, Switzerland.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Morita
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Immunology, Faculty of Health Science, Kyorin University, Tokyo, 192-8508, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Arae
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Pediatrics, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Unno
authors.affiliation: Laboratory for Cytokine Regulation, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Miyauchi
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Immune Regulation, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Sumika
authors.initials: S
authors.lastname: Toyama
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Nambu
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Oboki
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Department of Molecular Immunology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Tatsukuni
authors.initials: T
authors.lastname: Ohno
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Motomura
authors.affiliation: Department of Ophthalmology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Narushima
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kajiwara
authors.affiliation: Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Iikura
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Suto
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Immune Regulation, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Molecular Immunology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Laboratory for Immune Cell System, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Moro
authors.affiliation: Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos 7270, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos 7270, Switzerland.
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
authors.affiliation: Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Galli
authors.affiliation: Laboratory for Immune Cell System, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.affiliation: Laboratory for Cytokine Regulation, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan; Division of Molecular Pathology, Research Institute for Biological Sciences, Tokyo University of Sciences, Chiba 278-0022, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Animal Research Center, Tokyo Medical University, Tokyo 160-8402, Japan.
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan; Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan. Electronic address: snakae@ims.u-tokyo.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D004802:Eosinophilia / Q000139:chemically induced; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010206:Papain / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D039981:Pyroglyphidae / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: C556062:IL10 protein, mouse; C506536:IL33 protein, human; C506535:Il33 protein, mouse; D007376:Interleukin-2; D000067596:Interleukin-33; D007378:Interleukins; D016753:Interleukin-10; D019009:Proto-Oncogene Proteins c-kit; D010206:Papain