Elucidation of the mechanism of asthma condition deterioration in the obese environment and the establish of treatment development

• Project/Area Number: 16H06224
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Kazusa DNA Research Institute (2018); Chiba University (2016-2017)
• Principal Investigator: Endo Yusuke 公益財団法人かずさDNA研究所, 先端研究開発部, 室長 (80612192)
• Research Collaborator: NAKAYAMA TOSHINORI
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥25,350,000 (Direct Cost: ¥19,500,000、Indirect Cost: ¥5,850,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2017: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2016: ¥11,830,000 (Direct Cost: ¥9,100,000、Indirect Cost: ¥2,730,000)
• Keywords: 肥満 / 喘息 / Tpath2 / ILC2 / ACC1 / 脂質代謝 / アレルギー性皮膚炎 / Ｔｐａｔｈ２ / ＩＬＣ２ / 免疫学 / 細胞内代謝 / 脂質 / 病態医化学 / Tpath2細胞 / アレルギー・ぜんそく

Outline of Final Research Achievements

This study focused on pathogenic Th2 (Tpath2) cells and group 2 innate cells (ILC2), and aimed to understand the mechanism of onset and chronicity of obesity-induced asthma. The following contents were clarified within the research period. 1. The aggravated asthmatic condition in obese environment was observed. 2. An increase in Tpath2 cells was observed in lung tissue in an obese environment. An increase was also detected for ILC3. 3. It was shown that not only endogenous fatty acid synthesis but also the uptake of fatty acid from the environment is important for the functional acquisition of Tpath2 and ILC2. 4. Obesity-induced asthma was improved by inhibiting lipid metabolism of Tpath2 or ILC2.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果より、Tpath2やILC2など生体に有害となる細胞の特殊な「脂肪酸代謝」という観点から喘息の発症・慢性化メカニズムにアプローチすることで、脂肪酸もしくはその合成経路をターゲットとした治療法開発が可能となる。具体的には、ACC1や特定の脂肪酸代謝経路をターゲットとした創薬や脂肪酸自体の食習慣によって肥満誘導性喘息を改善する基盤の構築が可能となるのである。また、本研究の成果は、肥満誘導性の喘息治療に留まらず、他の慢性アレルギー疾患の誘導・慢性化メカニズムの解明・新規診断ツール・治療法の足がかりとなり、肥満誘導性の慢性炎症疾患の解明に大きく貢献できる。

Research Products

• [Journal Article] ACC1 determines memory potential of individual CD4+ T cells by regulating de novo fatty acid biosynthesis (2019)
  • Author(s): Yusuke Endo, Atsushi Onodera, Kazushige Obata-Ninomiya, Ryo Koyama-Nasu, Hikari K. Asou, Toshihiro Ito, Takeshi Yamamoto, Toshio Kanno, Takahiro Nakajima, Kenji Ishiwata, Hirotaka Kanuka, Damon J. Tumes, Toshinori Nakayama
  • Journal Title: Nature Metabolism Volume: 1(2) Issue: 2 Pages: 261-275
  • DOI: 10.1038/s42255-018-0025-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells (2018)
  • Author(s): Yamamoto, T., Endo, Y., Onodera, A., Hirahara, K., Asou, H., Nakajima, T., Kanno, T., Ouchi, Y., Uematsu, S., Nishimasu, H., Nureki, O., Tumes, D. J., Shimojo, N., and Nakayama, T.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4231-4231
  • DOI: 10.1038/s41467-018-06468-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCR6+ST2+ memory T helper 2 cells induced the expression of major basic protein in eosinophils to reduce the fecundity of helminth (2018)
  • Author(s): Obata-Ninomiya, K., Ishiwata, K., Nakano, H., Endo, Y., Ichikawa, T., Onodera, A., Hirahara, K., Okamoto, Y., Kanuka, H., Nakayama, T.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 42
  • DOI: 10.1073/pnas.1714731115
  • Peer Reviewed / Open Access
• [Journal Article] Maintenance of memory-type pathogenic Th2 cells in the pathophysiology of chronic inflammation (2018)
  • Author(s): Hirahara, K., Shinoda, K., Endo, Y., Ichikawa, T., and Nakayama, T
  • Journal Title: Inflammation and Regeneration Volume: 38 Issue: 1 Pages: 10-10
  • DOI: 10.1186/s41232-018-0067-8
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic regulation of T-helper cell differentiation, memory, and plasticity in allergic asthma (2017)
  • Author(s): Tumes Damon J.、Papadopoulos Magdalene、Endo Yusuke、Onodera Atsushi、Hirahara Kiyoshi、Nakayama Toshinori
  • Journal Title: Immunol. Rev Volume: 278 Issue: 1 Pages: 8-19
  • DOI: 10.1111/imr.12560
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The obesity-related pathology and Th17 cells. (2017)
  • Author(s): Endo, Y., Yokote, K., and Nakayama, T.
  • Journal Title: Cell. Mol. Life Sci. Volume: 74 Issue: 7 Pages: 1231-1245
  • DOI: 10.1007/s00018-016-2399-3
  • NAID: 40021094104
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Th2 cells in health and disease. (2016)
  • Author(s): Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K, Tumes DJ, Okamoto Y.
  • Journal Title: Annu Rev Immunol. Volume: 35 Issue: 1 Pages: 53-84
  • DOI: 10.1146/annurev-immunol-051116-052350
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Akt1-mediated Gata3 phosphorylation controls the repression of IFNγ in memory-type Th2 cells. (2016)
  • Author(s): Hosokawa H, Tanaka T, Endo Y, Kato M, Shinoda K, Suzuki A, Motohashi S, Matsumoto M, Nakayama K, Nakayama T.
  • Journal Title: Nat Commun. Volume: - Issue: 1 Pages: 11289-11289
  • DOI: 10.1038/ncomms11289
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells. (2016)
  • Author(s): Angela, M.,* Endo, Y.,* Asou, H. K., Yamamoto, T., Tumes, D. J., Tokuyama, H., Yokote, K., and Nakayama, T.
  • Journal Title: Nat. Commun. Volume: 7 Issue: 1 Pages: 13683-13683
  • DOI: 10.1038/ncomms13683
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 脂肪酸を基軸とする「代謝-免疫-疾患」スパイラルの分子機構解明 (2019)
  • Author(s): 遠藤 裕介
  • Organizer: 愛媛大学プロテオサイエンスシンポジウム
• [Presentation] Elucidation of the role of fatty acid metabolism in Th17 cell differentiation under obese conditions (2018)
  • Author(s): Yusuke Endo
  • Organizer: The 2nd Chiba University-UC San Diego Symposium “Mucosal Immunology, Allergy and Vaccine
  • Int'l Joint Research
• [Presentation] 脂肪酸を基軸とする「代謝-免疫-疾患」スパイラルの分子機構解明 (2018)
  • Author(s): 遠藤 裕介
  • Organizer: 東海大学医学会セミナー
• [Presentation] Elucidation of the role of fatty acid metabolism in Th17 cell differentiation under obese conditions. (2017)
  • Author(s): Endo, Y., and Nakayama, T.
  • Organizer: 7th International Workshop of Kyoto T Cell Conference,
  • Place of Presentation: 京都大学医学部・芝蘭会館（京都府京都市）
  • Year and Date: 2017-03-17
  • Int'l Joint Research
• [Presentation] Memory type pathogenic Th2 (Tpath2) cells in airway inflammation. (2017)
  • Author(s): Nakayama, T., Endo, Y., Shinoda, K., and Hirahara, K.
  • Organizer: 7th International Workshop of Kyoto T Cell Conference
  • Place of Presentation: 京都大学医学部・芝蘭会館（京都府京都市）
  • Year and Date: 2017-03-16
  • Int'l Joint Research
• [Presentation] Elucidation of the role of fatty acid metabolism in Th cell differentiation under obese conditions. (2017)
  • Author(s): Endo, Y.
  • Organizer: AAI Annual Meeting Immunology
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of the role of fatty acid metabolism in Th cell differentiation under obese conditions. (2017)
  • Author(s): Endo, Y.
  • Organizer: Leibniz-AMED Workshop on Chronic Inflammation, Infection and Healthy Aging
  • Int'l Joint Research / Invited
• [Presentation] Fatty acid metabolic reprogramming via mTOR-mediated induction of PPARγ directs early activation of T cells. (2016)
  • Author(s): Endo, Y., Yamamoto, T., Tumes, D. J., and Nakayama, T.
  • Organizer: 第45回日本免疫学会総会・学術集会
  • Place of Presentation: 沖縄コンベンションセンター(沖縄県宜野湾市)
  • Year and Date: 2016-12-07
• [Presentation] Obesity drives Th17 cell differentiation by inducing the carboxylase ACC1 and fatty acid biosynthesis. (2016)
  • Author(s): Endo, Y., and Nakayama, T.
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-01
• [Book] Chronic Inflammation Mechanisms and Regulation (2016)
  • Author(s): Endo, Y., Hirahara, K., Shinoda, K., Iinuma, T., Yamamoto, H., Motohashi, S., Okamoto, Y., and Nakayama, T.
  • Total Pages: 701
  • Publisher: SPRINGER NATURE
• [Remarks] かずさDNA研究所先端研究開発部オミックス医科学研究室
  • URL: http://www.kazusa.or.jp/laboratories/advanced-department/omics-lab/
• [Remarks] 千葉大学大学院医学研究院免疫発生学教室
  • URL: https://www.m.chiba-u.ac.jp/class/meneki/
• [Remarks] 千葉大学大学院医学研究院免疫発生学
  • URL: http://www.m.chiba-u.ac.jp/class/meneki/