Elucidation of the mechanism of T-bet-mediated induction of pulmonary alveolar proteinosis

• Project/Area Number: 16K15454
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Ishii Yukio 筑波大学, 医学医療系, 教授 (80272194)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肺胞蛋白症 / 転写因子 / T-bet / リンパ球 / マクロファージ / M-CSF / インターフェロンγ / インターフェロン / 動物モデル / Ｔ－ｂｅｔ / 内科

Outline of Final Research Achievements

Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by abnormal surfactant accumulation in the alveoli.Here we show a novel mechanism by which acquired PAP develops without dysregulation of GM-CSF signaling. Mice carrying T cells overexpressing T-bet spontaneously developed PAP with pulmonary inflammation. PAP development was found to associate with dysregulation of bone marrow monopoiesis that led to accumulation of bone marrow-driven inflammatory macrophages into the lung while reducing the number of alveolar macrophages. Administration of macrophage colony-stimulating factor restored the impairment of monocytic differentiation. Higher expression of T-bet was observed in the lung lesions of human secondary PAP. These findings suggest that unresolved pulmonary inflammation initiated by T-bet overexpressing T cells reorganizes the subpopulation of macrophages in the lung that results in a reduction of surfactant clearance in alveoli and thus development of PAP.

Academic Significance and Societal Importance of the Research Achievements

成人に発症する肺胞蛋白症は特発性と続発性に分けられる。近年特発性肺胞蛋白症の多くの症例で抗GM-CSF抗体が証明され、自己免疫性肺胞蛋白症として、その病態の理解も進んだ。一方、血液疾患等に伴う続発性肺胞蛋白症の病態生理は今尚不明であり、原疾患と相まってその予後は不良である。T-bet高発現マウスの肺胞蛋白症はGM-CSF非依存的であること、骨髄の異常を伴うこと、肺に炎症を伴うことなど、続発性肺胞蛋白症と類似する点が多く、今回解明した発症機構は続発性肺胞蛋白症の病態を理解する上で極めて重要と考える。続発性肺胞蛋白症は極めて稀な疾患で製薬会社の関心も薄く、同領域の研究はアカデミアの責務でもある。

Research Products

• [Journal Article] Transcription Factor T-bet Attenuates the Development of Elastase-induced Emphysema in Mice (2019)
  • Author(s): Hayashi Shigen、Matsuno Yosuke、Tsunoda Yoshiya、Sakurai Hirofumi、Kiwamoto Takumi、Morishima Yuko、Ishii Yukio、Yoh Keigyou、Takahashi Satoru、Hizawa Nobuyuki
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 61 Issue: 4 Pages: 525-536
  • DOI: 10.1165/rcmb.2018-0109oc
  • Peer Reviewed
• [Journal Article] Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice (2018)
  • Author(s): Sakurai Hirofumi、Morishima Yuko、Ishii Yukio、Yoshida Kazufumi、Nakajima Masayuki、Tsunoda Yoshiya、Hayashi Shih-Yuan、Kiwamoto Takumi、Matsuno Yosuke、Kawaguchi Mio、Yamamoto Masayuki、Hizawa Nobuyuki
  • Journal Title: Free Radical Biology and Medicine Volume: 129 Pages: 473-485
  • DOI: 10.1016/j.freeradbiomed.2018.10.400
  • Peer Reviewed
• [Journal Article] Notch signaling regulates cell density-dependent apoptosis of NIH 3T3 through an IL-6/STAT3 dependent mechanism (2018)
  • Author(s): Matsuno Yosuke、Kiwamoto Takumi、Morishima Yuko、Ishii Yukio、Hizawa Nobuyuki、Hogaboam Cory M.
  • Journal Title: European Journal of Cell Biology Volume: 97 Issue: 7 Pages: 512-522
  • DOI: 10.1016/j.ejcb.2018.09.001
  • Peer Reviewed / Open Access
• [Journal Article] Transcription elongation factor P-TEFb is involved in IL-17F signaling in airway smooth muscle cells. (2018)
  • Author(s): Nakajima Masayuki, Kawaguchi Mio, Matsuyama Masashi, Ota Kyoko, Fujita Jun, Matsukura Satoshi, Huang Shau-Ku, Morishima Yuko, Ishii Yukio, Satoh Hiroaki, Sakamoto Tohru, Hizawa Nobuyuki.
  • Journal Title: Int Arch Allergy Immunol Volume: 印刷中 Issue: 2 Pages: 83-90
  • DOI: 10.1159/000488154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL-17F induces IL-6 via TAK1-NFκB pathway in airway smooth muscle cells (2017)
  • Author(s): Masayuki Nakajima, Mio Kawaguchi, Kyoko Ota, Junichi Fujita, Satoshi Matsukura, Shau-Ku Huang, Yuko Morishima, Yukio Ishii, Hiroaki Satoh, Tohru Sakamoto, Nobuyuki Hizawa.
  • Journal Title: Immunity, Inflammation and Disease Volume: 3 Issue: 2 Pages: 1-8
  • DOI: 10.1002/iid3.149
  • NAID: 120007129102
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice. (2017)
  • Author(s): Ano S, Panariti A, Allard B, O'Sullivan M, McGovern TK, Hamamoto Y, Ishii Y, Yamamoto M, Powell WS, Martin JG.
  • Journal Title: Free Radic Biol Med Volume: 102 Pages: 1-15
  • DOI: 10.1016/j.freeradbiomed.2016.11.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10-induced modulation of phagocyte antifungal activity (2016)
  • Author(s): Haraguchi N, Kikuchi N, Morishima Y, Matsuyama M, Sakurai H, Shibuya A, Shibuya K, Taniguchi M, Ishii Y
  • Journal Title: Eur J Immunol Volume: 46 Issue: 7 Pages: 1691-1703
  • DOI: 10.1002/eji.201545987
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overexpression of RORγt enhances pulmonary inflammation after infection with Mycobacterium Avium. (2016)
  • Author(s): Matsuyama M, Ishii Y, Sakurai H, Ano S, Morishima Y, Yoh K, Takahashi S, Ogawa K, Hizawa N
  • Journal Title: PLoS One Volume: 11 Issue: 1 Pages: e0147064-e0147064
  • DOI: 10.1371/journal.pone.0147064
  • NAID: 120007127851
  • Peer Reviewed / Open Access
• [Presentation] Deletion of Elovl6 alters fatty acid composition in lung tissue and enhances allergic airway inflammation. (2019)
  • Author(s): Yoshida K, Morishima Y, Sakurai H, Sherpa M, Tsunoda Y, Nakajima M, Matsuyama M, Kiwamoto T, Matsuno Y, Ishii Y, Hizawa N.
  • Organizer: 2019 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] Role of PD-1 pathway in pulmonary MAC infection using mice model. (2019)
  • Author(s): Nakajima M, Matsuyama M, Kawaguchi M, Sherpa M, Yoshida K, Kiwamoto T, Matsuno Y, Morishima Y, Ishii Y, Hizawa N.
  • Organizer: 2019 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] Hyaluronan synthase 2 (HAS2) mediates airway inflammation and remodeling in chronic ovalbumin model of asthma. (2019)
  • Author(s): Sherpa M, Kiwamoto T, Tsunoda Y, Yoshida K, Osawa H, Nakajima M, Matsuyama M, Matsuno Y, Morishima Y, Ishii Y, Hizawa N.
  • Organizer: 2019 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] The role of elongation of very long chain fatty acids family member 6 in allergic airway inflammation. (2018)
  • Author(s): Yoshida K, Morishima Y, Sakurai H, Tsunoda Y, Nakajima M, Matsuyama M, Kiwamoto T, Matsuno Y, Ishii Y, Hizawa N
  • Organizer: 2018 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] ROS-Nrf2 pathway mediates the development of TGF-b1-induced epithelial-mesenchymal transition through the interaction with notch signaling. (2018)
  • Author(s): Matsuno Y, Matsuyama M, Kiwamoto T, Morishima Y, Ishii Y, Hizawa N
  • Organizer: 2018 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] Hyaluronan synthase 2 dysfunction induce severe eosinophilic airway inflammation via inflammatory cytokines and chemokines. (2018)
  • Author(s): Kiwamoto T, Tsunoda Y, Sherpa M, Sakurai H, Lin S, Matsuyama M, Matsuno Y, Morishima Y, Ishii Y, Hizawa N
  • Organizer: 2018 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] The role of T-bet in emphysema. (2017)
  • Author(s): Hayashi S, Matsuno Y, Tsunoda Y, Sakurai H, Kiwamoto T, Kawaguchi M, Morishima Y, Ishii Y, Hizawa N.
  • Organizer: 2017 International Conference of American Thoracic Society
  • Int'l Joint Research
• [Presentation] The effect of sulforaphane on airway dysfunction in mice after chlorine gas exposure. (2017)
  • Author(s): Ano S, Panariti A, Allard B, O’Sullivan M, McGovern TK, Hamamoto Y, Ishii Y, Powell WS, Martin JG.
  • Organizer: 2017 International Conference of American Thoracic Society
• [Presentation] 異常活性化T細胞による肺胞蛋白症発症機構の解明 (2016)
  • Author(s): 阿野哲士、菊池教大、石井幸雄
  • Organizer: 第25回ＰｎｅｕｍｏＦｏｒｕｍ
  • Place of Presentation: 経団連会館、東京都千代田区
  • Year and Date: 2016-11-05