The analysis of systemic sclerosis pathogenesis with mice lacking the Fli1 gene in various cell types

• Project/Area Number: 16H05366
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: The University of Tokyo
• Principal Investigator: Asano Yoshihide 東京大学, 医学部附属病院, 准教授 (60313029)
• Research Collaborator: Trojanowska Maria ; Zhuang Yuan
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 全身性強皮症 / 動物モデル / 自己免疫・炎症 / 血管障害 / 線維化 / 転写因子 / Fli1 / 血管内皮細胞 / B細胞 / 表皮細胞 / 免疫異常 / 皮膚科学 / 皮膚病態学

Outline of Final Research Achievements

Fli1 deficiency is a potential predisposing factor in the development of systemic sclerosis (SSc). To investigate the role of various cell types in the pathogenesis of SSc, we generated mice lacking the Fli1 gene in endothelial cells, epithelial cells, B cells, gamma delta T cells, regulatory T cells, adipocytes, megakaryocytes or myeloid cells by using loxp-Cre system. Of note, all the 8 strains of mice reproduced all or a part of the three cardinal pathological features of SSc, such as autoimmunity/inflammation, vasculopathy and tissue fibrosis. Since B cell- and myeloid cell-specific Fli1 knockout mice strictly recapitulated the three pathological features, these results suggest that B cells and myeloid cells play a central role in the development of SSc and the other cell types contribute to the induction of SSc clinical phenotype.

Academic Significance and Societal Importance of the Research Achievements

強皮症にはいまだ確立された治療法はないが、近年、抗IL-6受容体抗体と抗CD20抗体が皮膚硬化と間質性肺疾患の治療に有用であり、さらにM2マクロファージとB細胞の異常活性化がその病態形成において重要であることが示された。本研究では、骨髄細胞およびB細胞特異的Fli1欠失マウスにおいて強皮症の主要3病態が忠実に再現され、特にM2マクロファージとB細胞の異常活性化が重要であることを証明した。以上より、Fli1の発現異常に基づく動物モデルは強皮症の病態解析に有用であること、および8系統のモデルマウスを活用した解析は強皮症の病態解明と治療開発に大きく貢献できる可能性を秘めていることが明らかとなった。

Research Products

• [Int'l Joint Research] Northwestern University/Boston University(米国)
• [Int'l Joint Research] Boston University School of Medicine(米国)
• [Int'l Joint Research] Boston University School of Medicine(米国)
• [Journal Article] Prediction of therapeutic response before and during i.v. cyclophosphamide pulse therapy for interstitial lung disease in systemic sclerosis: A longitudinal observational study (2018)
  • Author(s): Sumida Hayakazu、Asano Yoshihide、Tamaki Zenshiro、Aozasa Naohiko、Taniguchi Takashi、Toyama Tetsuo、Takahashi Takehiro、Ichimura Yohei、Noda Shinji、Akamata Kaname、Saigusa Ryosuke、Miyazaki Miki、Kuwano Yoshihiro、Yanaba Koichi、Yoshizaki Ayumi、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 12 Pages: 1425-1433
  • DOI: 10.1111/1346-8138.14669
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Progranulin overproduction due to constitutively activated c-Abl/PKC-δ/Fli1 pathway contributes to the resistance of dermal fibroblasts to the anti-fibrotic effect of tumor necrosis factor-α in localized scleroderma (2018)
  • Author(s): Miyagawa Takuya、Ichimura Yohei、Nakamura Kouki、Hirabayashi Megumi、Yamashita Takashi、Saigusa Ryosuke、Miura Shunsuke、Takahashi Takehiro、Toyama Tetsuo、Taniguchi Takashi、Akamata Kaname、Yoshizaki Ayumi、Sato Shinichi、Asano Yoshihide
  • Journal Title: Journal of Dermatological Science Volume: 92 Issue: 2 Pages: 207-214
  • DOI: 10.1016/j.jdermsci.2018.09.005
  • Peer Reviewed
• [Journal Article] An orally-active adiponectin receptor agonist mitigates cutaneous fibrosis, inflammation and microvascular pathology in a murine model of systemic sclerosis (2018)
  • Author(s): Yamashita Takashi、Lakota Katja、Taniguchi Takashi、Yoshizaki Ayumi、Sato Shinichi、Hong Wen、Zhou Xingchun、Sodin-Semrl Snezn、Fang Feng、Asano Yoshihide、Varga John
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11843-11843
  • DOI: 10.1038/s41598-018-29901-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systemic sclerosis complicated with localized scleroderma-like lesions induced by Koebner phenomenon. (2018)
  • Author(s): Saigusa R, Asano Y, Yamashita T, Takahashi T, Nakamura K, Miura S, Ichimura Y, Toyama T, Taniguchi T, Sumida H, Tamaki Z, Miyazaki M, Yoshizaki A, Sato S.
  • Journal Title: J Dermatol Sci. Volume: 89 Issue: 3 Pages: 282-289
  • DOI: 10.1016/j.jdermsci.2017.12.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Possible pro-inflammatory role of heparin-binding epidermal growth factor-like growth factor in the active phase of systemic sclerosis (2017)
  • Author(s): Hirabayashi Megumi、Asano Yoshihide、Yamashita Takashi、Miura Shunsuke、Nakamura Kouki、Taniguchi Takashi、Saigusa Ryosuke、Takahashi Takehiro、Ichimura Yohei、Miyagawa Takuya、Yoshizaki Ayumi、Miyagaki Tomomitsu、Sugaya Makoto、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 2 Pages: 182-188
  • DOI: 10.1111/1346-8138.14088
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A potential contribution of psoriasin to vascular and epithelial abnormalities and inflammation in systemic sclerosis (2017)
  • Author(s): Takahashi T.、Asano Y.、Yamashita T.、Nakamura K.、Saigusa R.、Miura S.、Ichimura Y.、Toyama T.、Hirabayashi M.、Taniguchi T.、Yoshizaki A.、Sato S.
  • Journal Title: Journal of the European Academy of Dermatology and Venereology Volume: 32 Issue: 2 Pages: 291-297
  • DOI: 10.1111/jdv.14459
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma. (2017)
  • Author(s): Takehiro Takahashi, Yoshihide Asano, Koji Sugawara, Kouki Nakamura, Takashi Yamashita, Ryosuke Saigusa, Yohei Ichimura, Tetsuo Toyama, Takashi Taniguchi, Kaname Akamata, Shinji Noda, Ayumi Yoshizaki, Daisuke Tsuruta, Maria Trojanowska, and Shinichi Sato
  • Journal Title: Journal of Experimental Medicine Volume: 214 Issue: 4 Pages: 1129-1151
  • DOI: 10.1084/jem.20160247
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Systemic Sclerosis Dermal Fibroblasts Suppress Th1 Cytokine Production via Galectin-9 Overproduction due to Fli1 Deficiency (2017)
  • Author(s): Saigusa Ryosuke、Asano Yoshihide、Nakamura Kouki、Hirabayashi Megumi、Miura Shunsuke、Yamashita Takashi、Taniguchi Takashi、Ichimura Yohei、Takahashi Takehiro、Yoshizaki Ayumi、Miyagaki Tomomitsu、Sugaya Makoto、Sato Shinichi
  • Journal Title: J Invest Dermatol Volume: 137 Issue: 9 Pages: 1850-1859
  • DOI: 10.1016/j.jid.2017.04.035
  • Peer Reviewed
• [Journal Article] Fli1 Deficiency Induces CXCL6 Expression in Dermal Fibroblasts and Endothelial Cells, Contributing to the Development of Fibrosis and Vasculopathy in Systemic Sclerosis. (2017)
  • Author(s): Taniguchi T, Asano Y, Nakamura K, Yamashita T, Saigusa R, Ichimura Y, Takahashi T, Toyama T, Yoshizaki A, Sato S.
  • Journal Title: J Rheumatol. Volume: 44 Issue: 8 Pages: 1198-1205
  • DOI: 10.3899/jrheum.161092
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of transcription factor Fli1 deficiency on the regulation of angiogenesis (2017)
  • Author(s): Tetsuo Toyama, Yoshihide Asano, Takuya Miyagawa, Kouki Nakamura, Megumi Hirabayashi, Takashi Yamashita, Ryosuke Saigusa, Shunsuke Miura, Yohei Ichimura, Takehiro Takahashi, Takashi Taniguchi, Ayumi Yoshizaki, Shinichi Sato.
  • Journal Title: Experimental Dermatology Volume: in press Issue: 10 Pages: 912-918
  • DOI: 10.1111/exd.13341
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A possible implication of reduced levels of LIF, LIFR, and gp130 in vasculopathy related to systemic sclerosis. (2017)
  • Author(s): sclerosis. Taniguchi T, Miyagawa T, Tamaki Z, Nakamura K, Yamashita T, Saigusa R, Takahashi T, Toyama T, Ichimura Y, Yoshizaki A, Tada Y, Sugaya M, Kadono T, Sato S, Asano Y.
  • Journal Title: Arch Dermatol Res. Volume: 309 Issue: 10 Pages: 833-842
  • DOI: 10.1007/s00403-017-1786-4
  • Peer Reviewed / Int'l Joint Research
• [Presentation] A road from basic research to clinical trials - to meet patients’ DesiReS - (2018)
  • Author(s): Yoshihide Asano
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research / Invited
• [Presentation] Skin research provides a window into new aspects of systemic disease pathogenesis (2018)
  • Author(s): Yoshihide Asano
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research / Invited
• [Presentation] A new murine model of PAH associated with SSc - a potential tool to investigate the pathogenesis of this clinical entity (2018)
  • Author(s): Yoshihide Asano
  • Organizer: The 22nd Annual Scientific Meeting of the Japanese Heart Failure Society
  • Invited
• [Presentation] A new murine model of systemic sclerosis; Klf5+/-;Fli1+/- mice (2018)
  • Author(s): Yoshihide Asano
  • Organizer: The 6th International Conference on Biology and Pathobiology of KLF/Sp Transcription Factors
  • Int'l Joint Research / Invited
• [Presentation] Skin research provides a window into new aspects of systemic disease pathogenesis (2018)
  • Author(s): Yoshihide Asano
  • Organizer: 1st Joint Symposium of Department of Dermatology, Seoul National University and The University of Tokyo
  • Int'l Joint Research / Invited
• [Presentation] Fli1-deficient B cells contribute to the development of tissue fibrosis, vasculopathy, and immune abnormalities characteristic of systemic sclerosis (2017)
  • Author(s): Asano Y
  • Organizer: 15th International Workshop on Scleroderma Research
  • Int'l Joint Research / Invited
• [Presentation] Fli1 deficiency potentially regulates M2 macrophage / B cell axis in systemic sclerosis. (2017)
  • Author(s): Taniguchi T, Asano Y, Yamashita T, Nakamura K, Saigusa R, Ichimura Y, Takahashi T, Toyama T, Yoshizaki A, Sato S.
  • Organizer: The 42nd Annual Meeting of the Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Fli1 deficiency promotes CXCL13 expression from macrophages, contributing to the development of systemic sclerosis. (2017)
  • Author(s): Taniguchi T, Asano Y, Yamashita T, Nakamura K, Saigusa R, Ichimura Y, Takahashi T, Toyama T, Yoshizaki A, Sato S.
  • Organizer: 47th Annual ESDR Meeting 2017
  • Int'l Joint Research