Keap1-NRF2 system is a potential therapeutic strategy to regulate pediatric allergic disease.

• Project/Area Number: 17K16287
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: Nagashima Ryuichi 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん先進治療開発研究部, 研究技師 (20783707)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アレルギー / ILC2 / Nrf2 / 酸化ストレス / Keap1-Nrf2 / 免疫学 / アレルギー・ぜんそく

Outline of Final Research Achievements

The Keap1-NRF2 system plays a pivotal role in the oxidative-stress response. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. Here 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 highly proliferative capacity. In contrast, activating NRF2 with a chemical inducer decreased the viability of the wild-type, but not of the NRF2-deficient ILC2s. Using a mouse allergy model, we found that the activation of NRF2 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 suggest that NRF2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.

Academic Significance and Societal Importance of the Research Achievements

本研究は、小児期に懸念されるステロイド使用における問題点を克服するべく、比較的安全性の高いNRF2活性化剤に着目した。アレルギー性炎症を引き起こすILC2をステロイドと同等に減少させることから、NRF2活性化剤はステロイドに代替するアレルギー疾患制御薬として期待される。
またNRF2活性化剤は、アレルギーを惹起する活性化したILC2に有効であり、常在ILC2には無害であったことから、治療による副作用を軽減出来る可能性も考えられる。ステロイド耐性重症喘息患者に対する新規治療法としての可能性を切り開いた点で、社会的意義も高いと考えられる。

Research Products

• [Journal Article] Nrf2 Suppresses Allergic Lung Inflammation by Attenuating the Type 2 Innate Lymphoid Cell Response (2019)
  • Author(s): Nagashima Ryuichi、Kosai Hitomi、Masuo Masahiro、Izumiyama Keiko、Noshikawaji Taketo、Morimoto Motoko、Kumaki Satoru、Miyazaki Yasunari、Motohashi Hozumi、Yamamoto Masayuki、Tanaka Nobuyuki
  • Journal Title: The Journal of Immunology Volume: 202 Issue: 5 Pages: 1331-1339
  • DOI: 10.4049/jimmunol.1801180
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Nrf2 suppresses allergic lung inflammation by attenuating the type2-innate lymphoid cell response. (2018)
  • Author(s): Ryuichi Nagashima, Hitomi Kosai, Keiko Izumiyama, Nobuyuki Tanaka.
  • Organizer: The 3rd international conference on innate lymphoid cells (ILC2018)
  • Int'l Joint Research
• [Presentation] Nrf2 activation suppressed lung allergic inflammation induced by type2-innate lymphoid cells. (2017)
  • Author(s): Ryuichi Nagashima, Hozumi Motohashi, Nobuyuki Tanaka
  • Organizer: 第46回 日本免疫学会
• [Presentation] Nrf2活性化による2型自然リンパ球（ILC2）抑制現象の発見とステロイド抵抗性アレルギーに対する新規治療法への展開 (2017)
  • Author(s): 長島 隆一, 小斎 仁美, 田中 伸幸
  • Organizer: 第71回 細菌学会 東北支部総会