An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers

Hideaki Morita; Ken Arae; Hirotoshi Unno; Kousuke Miyauchi; Sumika Toyama; Aya Nambu; Keisuke Oboki; Tatsukuni Ohno; Kenichiro Motomura; Akira Matsuda; Sachiko Yamaguchi; Seiko Narushima; Naoki Kajiwara; Motoyasu Iikura; Hajime Suto; Andrew N J McKenzie; Takao Takahashi; Hajime Karasuyama; Ko Okumura; Miyuki Azuma; Kazuyo Moro; Cezmi A Akdis; Stephen J Galli; Shigeo Koyasu; Masato Kubo; Katsuko Sudo; Hirohisa Saito; Kenji Matsumoto; Susumu Nakae

doi:10.1016/j.immuni.2015.06.021

An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers

Immunity. 2015 Jul 21;43(1):175-86. doi: 10.1016/j.immuni.2015.06.021.

Authors

Hideaki Morita¹, Ken Arae², Hirotoshi Unno³, Kousuke Miyauchi⁴, Sumika Toyama⁵, Aya Nambu⁶, Keisuke Oboki⁷, Tatsukuni Ohno⁸, Kenichiro Motomura⁷, Akira Matsuda⁹, Sachiko Yamaguchi¹⁰, Seiko Narushima¹⁰, Naoki Kajiwara⁷, Motoyasu Iikura¹¹, Hajime Suto¹², Andrew N J McKenzie¹³, Takao Takahashi¹⁴, Hajime Karasuyama¹⁵, Ko Okumura¹², Miyuki Azuma¹⁶, Kazuyo Moro¹⁷, Cezmi A Akdis¹⁸, Stephen J Galli¹⁹, Shigeo Koyasu²⁰, Masato Kubo²¹, Katsuko Sudo²², Hirohisa Saito⁷, Kenji Matsumoto⁷, Susumu Nakae²³

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Laboratory for Cytokine Regulation, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan.
⁵ 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.
⁶ 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.
⁷ Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
⁸ 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.
⁹ Department of Ophthalmology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
¹⁰ Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
¹¹ Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
¹² Atopy Research Center, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
¹³ MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.
¹⁴ Department of Pediatrics, Keio University School of Medicine, Tokyo, 160-8582, Japan.
¹⁵ 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.
¹⁶ Department of Molecular Immunology, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
¹⁷ 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.
¹⁸ Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos 7270, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos 7270, Switzerland.
¹⁹ Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
²⁰ Laboratory for Immune Cell System, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Kanagawa 230-0045, Japan.
²¹ 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.
²² Animal Research Center, Tokyo Medical University, Tokyo 160-8402, Japan.
²³ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bronchoalveolar Lavage Fluid / cytology
Bronchoalveolar Lavage Fluid / immunology
Cells, Cultured
Eosinophilia / chemically induced
Humans
Inflammation / immunology*
Interleukin-10 / immunology
Interleukin-2 / genetics
Interleukin-2 / immunology*
Interleukin-33
Interleukins / genetics
Interleukins / immunology*
Interleukins / pharmacology
Lung / cytology
Lung / immunology
Lymphocyte Activation / drug effects
Lymphocyte Activation / immunology
Mast Cells / immunology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Papain / pharmacology
Proto-Oncogene Proteins c-kit / genetics
Pyroglyphidae / immunology
T-Lymphocytes, Regulatory / immunology*
Th2 Cells / immunology

Substances

IL10 protein, mouse
IL33 protein, human
Il33 protein, mouse
Interleukin-2
Interleukin-33
Interleukins
Interleukin-10
Proto-Oncogene Proteins c-kit
Papain

Abstract

Publication types

MeSH terms

Substances

Grants and funding