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Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response

Ryuichi Nagashima, Hitomi Kosai, Masahiro Masuo, Keiko Izumiyama, Taketo Noshikawaji, Motoko Morimoto, Satoru Kumaki, Yasunari Miyazaki, Hozumi Motohashi, Masayuki Yamamoto and Nobuyuki Tanaka
J Immunol January 23, 2019, ji1801180; DOI: https://doi.org/10.4049/jimmunol.1801180
Ryuichi Nagashima
*Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Medeshima-Shiode, Natori 981-1293, Japan;
†Division of Tumor Immunobiology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan;
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Hitomi Kosai
*Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Medeshima-Shiode, Natori 981-1293, Japan;
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Masahiro Masuo
‡Department of Respiratory Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8510, Japan;
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Keiko Izumiyama
*Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Medeshima-Shiode, Natori 981-1293, Japan;
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Taketo Noshikawaji
*Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Medeshima-Shiode, Natori 981-1293, Japan;
†Division of Tumor Immunobiology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan;
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Motoko Morimoto
§School of Food, Agricultural and Environmental Sciences, Miyagi University, 2-2-1 Hatadate, Sendai 982-0215, Japan;
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Satoru Kumaki
¶Department of Pediatrics, Sendai Medical Center, 2-8-8 Miyagino, Sendai 983-8520, Japan;
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Yasunari Miyazaki
‡Department of Respiratory Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8510, Japan;
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Hozumi Motohashi
‖Division of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University 4-1 Seiryo-machi, Sendai 980-8575, Japan; and
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Masayuki Yamamoto
#Division of Medical Biochemistry, Tohoku University Graduate School of Medicine 2-1 Seiryo-machi, Sendai 980-8575, Japan
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Nobuyuki Tanaka
*Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Medeshima-Shiode, Natori 981-1293, Japan;
†Division of Tumor Immunobiology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Sendai 980-8575, Japan;
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Abstract

The Keap1–Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1–Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of the wild-type but not of the Nrf2-deficient ILC2s. This effect on viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3–dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33 administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the number of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response by determining the survival and death of ILC2s, and these findings suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.

Footnotes

  • This work was supported in part by Grant-in-Aids from Advanced Research and Development Programs for Medical Innovation (chronic inflammation) to M.Y., H.M., and N.T., Ministry of Education, Culture, Sports, Science and Technology-Japan Society for the Promotion of Science KAKENHI Grants 17K16287 to R.N. and 18H02701 to N.T., a Naito Foundation grant to N.T., and a grant from the Cooperative Research Project Program of the Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University.

  • The online version of this article contains supplemental material.

  • Received August 24, 2018.
  • Accepted December 24, 2018.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response
Ryuichi Nagashima, Hitomi Kosai, Masahiro Masuo, Keiko Izumiyama, Taketo Noshikawaji, Motoko Morimoto, Satoru Kumaki, Yasunari Miyazaki, Hozumi Motohashi, Masayuki Yamamoto, Nobuyuki Tanaka
The Journal of Immunology January 23, 2019, ji1801180; DOI: 10.4049/jimmunol.1801180

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Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response
Ryuichi Nagashima, Hitomi Kosai, Masahiro Masuo, Keiko Izumiyama, Taketo Noshikawaji, Motoko Morimoto, Satoru Kumaki, Yasunari Miyazaki, Hozumi Motohashi, Masayuki Yamamoto, Nobuyuki Tanaka
The Journal of Immunology January 23, 2019, ji1801180; DOI: 10.4049/jimmunol.1801180
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