Investigation of the mechanism of secondary PAP using Bach2-deficient mice

• Project/Area Number: 16H06640
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Respiratory organ internal medicine
• Research Institution: Tohoku University
• Principal Investigator: Shibuya Risa 東北大学, 医学系研究科, 非常勤講師 (90778408)
• Project Period (FY): 2016-08-26 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肺胞蛋白症 / 肺胞マクロファージ / Bach2 / Bach1 / 免疫 / 炎症 / 続発性肺胞蛋白症 / 慢性炎症 / 免疫学 / 遺伝子 / 発現制御

Outline of Final Research Achievements

Using mice lacking Bach2 in specific cell types, we found that the Pulmonary alveolar proteinosis (PAP)-phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyper-activated T cells in Bach2-deficient mice restored normal function of alveolar macrophages (AMs) and ameliorated PAP. Hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells in AMs, in which Bach2 then bound to regulatory regions of these genes. We conclude that Bach2 is critical for the maintenance of AM identity in inflammatory environments.
The Bach1/Bach2 double-deficient mice showed a more rapid and severe PAP phenotype than Bach2-deficient mice with abnormal AMs, whereas the Bach1-deficient mice did not develop any pulmonary disease. Bach1 and Bach2 work in a complementary manner to maintain the normal function of the AMs and surfactant homeostasis in the lung.

Research Products

• [Journal Article] Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis. (2017)
  • Author(s): Ebina-Shibuya R, Matsumoto M, Kuwahara M, Jang KJ, Sugai M, Ito Y, Funayama R, Nakayama K, Sato Y, Ishii N, Okamura Y, Kinoshita K, Kometani K, Kurosaki T, Muto A, Ichinose M, Yamashita M, Igarashi K.
  • Journal Title: The Journal of biological chemistry Volume: 292 Issue: 44 Pages: 18098-18112
  • DOI: 10.1074/jbc.m117.808535
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The double knockout of Bach1 and Bach2 in mice reveals shared compensatory mechanisms in regulating alveolar macrophage function and lung surfactant homeostasis. (2016)
  • Author(s): Ebina-Shibuya, R., Watanabe-Matsui, M., Matsumoto, M., Itoh-Nakadai, A., Funayama, R., Nakayama, K., Muto, A., and Igarashi, K.
  • Journal Title: The Journal of Biochemistry Volume: 160 Issue: 6 Pages: 333-334
  • DOI: 10.1093/jb/mvw041
  • NAID: 40021050454
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Bach2 keeps homeostasis in lung by maintaining the function of alveolar macrophages in inflammatory environment (2017)
  • Author(s): Risa Ebina-Shibuya, Mitsuyo Matsumoto, Makoto Kuwahara, Kyoung-Jin Jang, Manabu Sugai, Yoshiaki Ito, Ryo Funayama, Keiko Nakayama, Yuki Sato, Naoto Ishii, Yasunobu Okamura, Kengo Kinoshita, Kohei Kometani, Tomohiro Kurosaki, Akihiko Muto, Masakazu Ichinose, Masakatsu Yamashita, Kazuhiko Igarashi
  • Organizer: The 2017 Japan-NIH joint Symposium
  • Place of Presentation: 東北大学星陵キャンパス 星陵オーディトリアム (仙台)
  • Year and Date: 2017-02-15
  • Int'l Joint Research
• [Presentation] Bach2 maintains homeostasis in the lung by modulationg the inflammatory interaction between macrophages and T cells (2017)
  • Author(s): Risa Ebina-Shibuya, Mitsuyo Matsumoto, Yuki Sato, Keiko Nakayama, Naoto Ishii, Kengo Kinoshita, Tomohiro Kurosaki, Akihiko Muto, Masakazu Ichinose, MasakatsuYamashita, Kazuhiko Igarashi
  • Organizer: The 19th Takeda Science Foundation Symposium on Bioscience
  • Place of Presentation: 武田薬品研修所 (大阪)
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] Bach2 maintains homeostasis in the lung by modulationg the inflammatory interaction between macrophages and T cells (2017)
  • Author(s): Risa Ebina-Shibuya
  • Organizer: The 19th Takeda Science Foundation Symposium on Bioscience
  • Int'l Joint Research
• [Presentation] Bach2 keeps homeostasis in lung by maintaining the function of alveolar macrophages in inflammatory environment (2017)
  • Author(s): Risa Ebina-Shibuya
  • Organizer: The 2017 Japan-NIH joint Symposium
  • Int'l Joint Research