An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers
Open accessAbstract
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.
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Type 2 ILCs are found in AR, where they closely interact with epithelial and other cells controlling the mucosal environment.
“Type 2 ILCs are found in AR, where they closely interact with epithelial and other cells controlling the mucosal environment.”
From International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (2018) · cites this paper as [375]
The Results section (“NH Cells Contribute to Protease-Mediated Eosinophilia”; page unavailable) identifies lung natural helper cells as ILC2s and describes their activation by IL-33 released from alveolar epithelial cells in a mouse airway-inflammation model. The paper mentions rhinitis in its Introduction as an allergic disorder, but it does not establish that ILC2s are found in allergic rhinitis or describe their interactions in the nasal mucosa. (LLM, conf=0.86)
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Schmitz, J., Owyang, A. M., Oldham, E. R., Song, Y., Murphy, E., McClanahan, T. K., Zurawski, G., Moshrefi, M., Qin, J., Li, X., et al. (2005) · Immunity · doi:10.1016/j.immuni.2005.09.015 · Cited by 3,701 · see citing works
Regulatory T cells: mechanisms of differentiation and function
Josefowicz, S. Z., Lu, L.-F., & Rudensky, A. Y. (2012) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141623 · Cited by 2,866 · see citing works
Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells
Moro, K., Yamada, T., Tanabe, M., Takeuchi, T., Ikawa, T., Kawamoto, H., Furusawa, J.-I., Ohtani, M., Fujii, H., & Koyasu, S. (2009) · Nature · doi:10.1038/nature08636 · Cited by 1,994 · see citing works
Self-citationHammad, H., Chieppa, M., Perros, F., Willart, M. A. M., Germain, R. N., & Lambrecht, B. N. (2009) · Nature Medicine · doi:10.1038/nm.1946 · Cited by 1,141 · see citing works
IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system
Sanada, S., Hakuno, D., Higgins, L., Schreiter, E. R., McKenzie, A. N. J., & Lee, R. T. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30634 · Cited by 1,053 · see citing works
Self-citationA mechanism for the initiation of allergen-induced T helper type 2 responses
Sokol, C. L., Barton, G. M., Farr, A. G., & Medzhitov, R. M. (2007) · Nature Immunology · doi:10.1038/ni1558 · Cited by 964 · see citing works
Halim, T. Y. F., Krauss, R., Sun, A. C., & Takei, F. (2012) · Immunity · doi:10.1016/j.immuni.2011.12.020 · Cited by 805 · see citing works
Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions
Wan, H., Winton, H. L., Soeller, C., Tovey, E. R., Gruenert, D. C., Thompson, P. J., Stewart, G. A., Taylor, G. W., Garrod, D. R., Cannell, M. B., et al. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5844 · Cited by 775 · see citing works
Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein
Trompette, A., Divanovic, S., Visintin, A., Blanchard, C., Hegde, R. S., Madan, R., Thorne, P. S., Wills-Karp, M. A., Gioannini, T. L., Weiss, J. P., et al. (2008) · Nature · doi:10.1038/nature07548 · Cited by 761 · see citing works
Mast cells are essential intermediaries in regulatory T-cell tolerance
Lu, L.-F., Lind, E. F., Gondek, D. C., Bennett, K. A., Gleeson, M. W., Pino-Lagos, K., Scott, Z. A., Coyle, A. J., Reed, J. L., Van Snick, J., et al. (2006) · Nature · doi:10.1038/nature05010 · Cited by 751 · see citing works
IL-33 is a crucial amplifier of innate rather than acquired immunity
Oboki, K., Ohno, T., Kajiwara, N., Arae, K., Morita, H., Ishii, A., Nambu, A., Abe, T., Kiyonari, H., Matsumoto, K., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003059107 · Cited by 655 · see citing works
Self-citationThe Transcription Factor GATA3 Is Essential for the Function of Human Type 2 Innate Lymphoid Cells
Mjösberg, J., Bernink, J. H., Golebski, K., Karrich, J. J., Peters, C. P., Blom, B., Velde, A. A. T., Fokkens, W. J., van Drunen, C. M., & Spits, H. (2012) · Immunity · doi:10.1016/j.immuni.2012.08.015 · Cited by 638 · see citing works
IL-1 Receptor Accessory Protein and ST2 Comprise the IL-33 Receptor Complex
Chackerian, A. A., Oldham, E. R., Murphy, E. E., Schmitz, J., Pflanz, S., & Kastelein, R. A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.4.2551 · Cited by 508 · see citing works
Grimbaldeston, M. A., Nakae, S., Kalesnikoff, J., Tsai, M. M., & Galli, S. J. (2007) · Nature Immunology · doi:10.1038/ni1503 · Cited by 486 · see citing works
Self-citationKondo, Y., Yoshimoto, T., Yasuda, K., Futatsugi‐Yumikura, S., Morimoto, M., Hayashi, N., Hoshino, T., Fujimoto, J., & Nakanishi, K. (2008) · International Immunology · doi:10.1093/intimm/dxn037 · Cited by 478 · see citing works
Chua, K. Y., Stewart, G. A., Thomas, W. R., Simpson, R. J., Dilworth, R. J., Plozza, T. M., & Turner, K. J. (1988) · The Journal of Experimental Medicine · doi:10.1084/jem.167.1.175 · Cited by 472 · see citing works
IL-33 exacerbates antigen-induced arthritis by activating mast cells
Xu, D., Jiang, H., Kewin, P., Li, Y., Mu, R., Fraser, A. R., Pitman, N. I., Kurowska‐Stolarska, M., McKenzie, A. N. J., McInnes, I. B., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801898105 · Cited by 465 · see citing works
Self-citationPichery, M., Mirey, E., Mercier, P., Lefrançais, E., Dujardin, A., Ortéga, N., & Girard, J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101977 · Cited by 463 · see citing works
Kurowska‐Stolarska, M., Kewin, P., Murphy, G., Russo, R. C., Stolarski, B., Garcia, C. C., Komai‐Koma, M., Pitman, N. I., Li, Y., McKenzie, A. N. J., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.7.4780 · Cited by 461 · see citing works
Self-citationContinuous exposure to house dust mite elicits chronic airway inflammation and structural remodeling
Johnson, J. R., Wiley, R. E., Fattouh, R., Swirski, F. K., Gajewska, B. U., Coyle, A. J., Gutierrez-Ramos, J.-C., Ellis, R., Inman, M. D., & Jordana, M. (2004) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200308-1094oc · Cited by 435 · see citing works
Orchestrating house dust mite-associated allergy in the lung
Gregory, L. G., & Lloyd, C. M. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.06.006 · Cited by 420 · see citing works
Gri, G., Piconese, S., Frossi, B., Manfroi, V., Merluzzi, S., Tripodo, C., Viola, A., Odom, S., Rivera, J., Colombo, M. P., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.08.018 · Cited by 390 · see citing works
IL-33 can promote survival, adhesion and cytokine production in human mast cells
Iikura, M., Suto, H., Kajiwara, N., Oboki, K., Ohno, T., Okayama, Y., Saito, H., Galli, S. J., & Nakae, S. (2007) · Laboratory Investigation · doi:10.1038/labinvest.3700663 · Cited by 370 · see citing works
Self-citationIL-33 induces IL-13 production by mouse mast cells independently of IgE-FcεRI signals
Ho, L. H., Ohno, T., Oboki, K., Kajiwara, N., Suto, H., Iikura, M., Okayama, Y., Akira, S., Saito, H., Galli, S. J., et al. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0407200 · Cited by 285 · see citing works
Self-citationMast cells enhance T cell activation: Importance of mast cell-derived TNF
Nakae, S., Suto, H., Kakurai, M., Sedgwick, J. D., Tsai, M. M., & Galli, S. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501912102 · Cited by 254 · see citing works
Self-citationHardman, C. S., Panova, V., & McKenzie, A. N. J. (2012) · European Journal of Immunology · doi:10.1002/eji.201242863 · Cited by 242 · see citing works
Self-citationHart, P. H., Grimbaldeston, M. A., Swift, G. J., Jaksic, A., Noonan, F. P., & Finlay-Jones, J. J. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.12.2045 · Cited by 241 · see citing works
Widespread Immunological Functions of Mast Cells: Fact or Fiction?
Rodewald, H.-R., & Feyerabend, T. B. (2012) · Immunity · doi:10.1016/j.immuni.2012.07.007 · Cited by 240 · see citing works
Augmentation of Permeability in the Bronchial Epithelium by the House Dust Mite Allergen Der p1
Herbert, C. A., King, C. M., Ring, P. C., Holgate, S. T., Stewart, G. A., Thompson, P. J., & Robinson, C. (1995) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb.12.4.7695916 · Cited by 228 · see citing works
Piconese, S., Gri, G., Tripodo, C., Musio, S., Gorzanelli, A., Frossi, B., Pedotti, R., Pucillo, C. E. M., & Colombo, M. P. (2009) · Blood · doi:10.1182/blood-2009-05-220004 · Cited by 211 · see citing works
New models for analyzing mast cell functions in vivo
Reber, L. L., Marichal, T., & Galli, S. J. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.09.008 · Cited by 188 · see citing works
Self-citationKamijo, S., Takeda, H., Tokura, T., Suzuki, M., Inui, K., Hara, M., Matsuda, H., Matsuda, A., Oboki, K., Ohno, T., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201212 · Cited by 167 · see citing works
Self-citationKashiwakura, J., Yokoi, H., Saito, H., & Okayama, Y. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.8.5247 · Cited by 165 · see citing works
Self-citationOtsuka, A., Kubo, M., Honda, T., Egawa, G., Nakajima, S., Tanizaki, H., Kim, B., Matsuoka, S., Watanabe, T., Nakae, S., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025538 · Cited by 144 · see citing works
Self-citationMast Cell Interleukin-2 Production Contributes to Suppression of Chronic Allergic Dermatitis
Hershko, A. Y., Suzuki, R., Charles, N., Álvarez‐Errico, D., Sargent, J. L., Laurence, A. D. J., & Rivera, J. (2011) · Immunity · doi:10.1016/j.immuni.2011.07.013 · Cited by 138 · see citing works
Mast Cell-Dependent Down-Regulation of Antigen-Specific Immune Responses by Mosquito Bites
Depinay, N., Hacini, F., Beghdadi, W., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.7.4141 · Cited by 134 · see citing works
Critical Role of p38 and GATA3 in Natural Helper Cell Function
Furusawa, J.-I., Moro, K., Motomura, Y., Okamoto, K., Zhu, J., Takayanagi, H., Kubo, M., & Koyasu, S. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300379 · Cited by 134 · see citing works
Self-citationNakamura, T., Hirasawa, Y., Takai, T., Mitsuishi, K., Okuda, M., Kato, T., Okumura, K., Ikeda, S., & Ogawa, H. (2006) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700584 · Cited by 95 · see citing works
Self-citationA new mechanism regulating the initiation of allergic airway inflammation
Kiss, A., Montes, M., Susarla, S. C., Gyllenbäck, E. J., Drouin, S. M., Wetsel, R. A., Yao, Z., Martin, R., Hamzeh, N. Y., Adelagun, R., et al. (2007) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2007.04.025 · Cited by 69 · see citing works
Mast cells suppress murine GVHD in a mechanism independent of CD4+CD25+ regulatory T cells
Leveson-Gower, D. B., Sega, E. I., Kalesnikoff, J., et al. (2013) · Blood · doi:10.1182/blood-2013-08-519157 · Cited by 56 · see citing works
Occupational asthma after inhalation of dust of the proteolytic enzyme, papain.
Milne, J., & Brand, S. (1975) · Occupational and Environmental Medicine · doi:10.1136/oem.32.4.302 · Cited by 52 · see citing works
Canine models of asthma and COPD
Chapman, R. W. (2008) · Pulmonary Pharmacology & Therapeutics · doi:10.1016/j.pupt.2008.01.003 · Cited by 46 · see citing works
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- Authors
- Morita, H., Arae, K., Unno, H., Miyauchi, K., Toyama, S., Nambu, A., Oboki, K., Ohno, T., Motomura, K., Matsuda, A., Yamaguchi, S., Narushima, S., Kajiwara, N., Iikura, M., Suto, H., McKenzie, A. N. J., Takahashi, T., Karasuyama, H., Okumura, K., Azuma, M., Moro, K., Akdis, C. A., Galli, S. J., Koyasu, S., Kubo, M., Sudo, K., Saito, H., Matsumoto, K., & Nakae, S.
- Affiliations
- University of Zurich (CH)
- Kyorin University (JP)
- Jikei University School of Medicine (JP)
- RIKEN (JP)
- Tokyo Medical and Dental University (JP)
- Juntendo University (JP)
- National Research Institute for Child Health and Development (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- National Center for Global Health and Medicine (JP)
- MRC Laboratory of Molecular Biology (GB)
- Keio University (JP)
- Japan Science and Technology Agency (JP)
- Stanford Medicine (US)
- Tokyo University of Science (JP)
- Tokyo Medical University (JP)
- Corresponding author
- Nakae, Susumu
- ORCID
- Morita, Hideaki
- Unno, Hirotoshi
- Toyama, Sumika
- Nambu, Aya
- Oboki, Keisuke
- Ohno, Tatsukuni
- Motomura, Kenichiro
- Matsuda, Akira
- Narushima, Seiko
- Iikura, Motoyasu
- Suto, Hajime
- McKenzie, Andrew N.J.
- Takahashi, Takao
- Karasuyama, Hajime
- Okumura, Ko
- Azuma, Miyuki
- Moro, Kazuyo
- Galli, Stephen J.
- Koyasu, Shigeo
- Kubo, Masato
- Sudo, Katsuko
- Saito, Hirohisa
- Matsumoto, Kenji
- Nakae, Susumu
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 43
- Issue
- 1
- Pages
- 175-186
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4533925
- OpenAlex
- W1497519679
- Cited by
- 274
- References
- 42
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 16 · 2023: 23 · 2022: 24 · 2021: 27 · 2020: 33 · 2019: 24 · 2018: 41 · 2017: 41 · 2016: 20 · 2015: 4
- FWCI
- 17.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Japan Science and Technology Agency
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Ministry of Health, Labour and Welfare, Japan
- Banyu Life Science Foundation International
- Swiss National Science Foundation (320030-140772)
- NIH (AI070813, AI023990, CA072074, U19AI104209)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Keywords
- IL-33, mast cells, interleukin-2, regulatory T cells, papain, allergic airway inflammation, airway eosinophilia, natural helper cells, ILC2, Th2 cytokines, epithelial barrier disruption, anti-inflammatory pathways
- MeSH terms
- Interleukin-33, Animals, Bronchoalveolar Lavage Fluid, Cells, Cultured, Eosinophilia, Humans, Inflammation, Interleukin-2, Interleukins, Lung, Lymphocyte Activation, Mast Cells, Mice, Inbred C57BL, Papain, Interleukin-10, Mice, Knockout, Th2 Cells, Proto-Oncogene Proteins c-kit, Pyroglyphidae, T-Lymphocytes, Regulatory, Mice
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