The role of transcription factor Fli1 in macrophage polarization in patients with systemic sclerosis

• Project/Area Number: 25461663
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• 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)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 全身性強皮症 / 免疫異常 / 炎症 / 血管障害 / 線維化 / マクロファージ / 転写因子

Outline of Final Research Achievements

Systemic sclerosis (SSc) is characterized by three pathological features, including immune abnormalities/inflammation, vasculopathy, and fibrosis. A series of our studies demonstrated that Fli1 deficiency contributes to the development of vasculopathy and fibrosis of SSc, but the role of Fli1 deficiency in immune abnormalities/inflammation still remains unknown. Therefore, to address this issue, we here investigated the impact of Fli1 deficiency on myeloid cells. Our results demonstrated the following findings: (i) Fli1 deficiency promotes the differentiation of macrophages into M2 subtype, (ii) myeloid cell-specific Fli1 knockout (Fli1 MyeKO) mice spontaneously develop dermal fibrosis due to endothelial-to-mesenchyaml transition following initial vascular changes, (iii) Fli1 MyeKO mice exhibit Th2/Th17-skewed immune polarization. Taken together, these results indicate that myeloid Fli1 deficiency is involved in the development of the three cardinal pathological features of SSc.

Research Products

• [Int'l Joint Research] ボストン大学(米国)
• [Journal Article] A potential contribution of altered cathepsin L expression to the development of dermal fibrosis and vasculopathy in systemic sclerosis. (2016)
  • Author(s): Yamashita T, Asano Y, Taniguchi T, Nakamura K, Saigusa R, Takahashi T, Ichimura Y, Toyama T, Yoshizaki A, Miyagaki T, Sugaya M, Sato S.
  • Journal Title: Exp Dermatol. Volume: 25 Issue: 4 Pages: 287-292
  • DOI: 10.1111/exd.12920
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fli1 deficiency contributes to the downregulation of endothelial protein C receptor in systemic sclerosis: a possible role in prothrombotic conditions. (2016)
  • Author(s): Saigusa R, Asano Y, Yamashita T, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Yoshizaki A, Miyagaki T, Sugaya M, Sato S.
  • Journal Title: Br J Dermatol. Volume: 174 Issue: 2 Pages: 338-347
  • DOI: 10.1111/bjd.14183
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Progranulin Overproduction Due to Fli-1 Deficiency Contributes to the Resistance of Dermal Fibroblasts to Tumor Necrosis Factor in Systemic Sclerosis. (2015)
  • Author(s): Ichimura Y, Asano Y, Akamata K, Noda S, Taniguchi T, Takahashi T, Toyama T, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: Arthritis Rheumatol. Volume: 67 Issue: 12 Pages: 3245-5355
  • DOI: 10.1002/art.39312
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A possible contribution of lipocalin-2 to the development of dermal fibrosis, pulmonary vascular involvement and renal dysfunction in systemic sclerosis. (2015)
  • Author(s): Takehiro Takahashi, Yoshihide Asano, Shinji Noda, Naohiko Aozasa, Kaname Akamata, Takashi Taniguchi, Yohei Ichimura, Tetsuo Toyama, Hayakazu Sumida, Yoshihiro Kuwano, Yayoi Tada, Makoto Sugata, Takafumi Kadono, Shinichi Sato
  • Journal Title: British Journal of Dermatology Volume: 173 Issue: 3 Pages: 681-9
  • DOI: 10.1111/bjd.13779
  • Peer Reviewed
• [Journal Article] Endothelin receptor blockade ameliorates vascular fragility in endothelial cell-specific Fli1 knockout mice by increasing Fli1 DNA-binding ability. (2015)
  • Author(s): Akamata K, Asano Y, Yamashita T, Noda S, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Trojanowska M, Sato S.
  • Journal Title: Arthritis Rheumatol. Volume: - Issue: 5 Pages: 1335-1344
  • DOI: 10.1002/art.39062
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Increased expression of chemerin in endothelial cells due to Fli1 deficiency may contribute to the development of digital ulcers in systemic sclerosis. (2015)
  • Author(s): Akamata K, Asano Y, Taniguchi T, Yamashita T, Saigusa R, Nakamura K, Noda S, Aozasa N, Toyama T, Takahashi T, Ichimura Y, Sumida H, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Rheumatology (Oxford). Volume: 54 Issue: 7 Pages: 1308-1316
  • DOI: 10.1093/rheumatology/keu479
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fibrosis, vascular activation, and immune abnormalities resembling systemic sclerosis in bleomycin-treated Fli-1-haploinsufficient mice. (2015)
  • Author(s): Taniguchi T, Asano Y, Akamata K, Noda S, Takahashi T, Ichimura Y, Toyama T, Trojanowska M, Sato S.
  • Journal Title: Arthritis Rheumatol. Volume: 67 Issue: 2 Pages: 517-526
  • DOI: 10.1002/art.38948
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis (2014)
  • Author(s): Noda, S
  • Journal Title: Nat Commun Volume: 5 Issue: 1 Pages: 5797-5797
  • DOI: 10.1038/ncomms6797
  • Peer Reviewed / Open Access
• [Journal Article] Bosentan reverses the pro-fibrotic phenotype of systemic sclerosis dermal fibroblasts via increasing DNA binding ability of transcription factor Fli1. (2014)
  • Author(s): Akamata K, Asano Y, et al.
  • Journal Title: Arthritis Res Ther. Volume: 16
  • Peer Reviewed
• [Journal Article] Fli1 deficiency contributes to the suppression of endothelial CXCL5 expression in systemic sclerosis. (2014)
  • Author(s): Ichimura Y, AsanoY, et al.
  • Journal Title: Arch Dermatol Res. Volume: 未定
  • Peer Reviewed
• [Journal Article] Decreased cathepsin V expression due to Flil deficiency contributes to the development of dermal fibrosis and proliferative vasculopathy in systemic sclerosis. (2013)
  • Author(s): Noda S, Asano Y, Takahashi T, Akamata K, Aozasa N, Taniguchi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S
  • Journal Title: Rheumatology (Oxford) Volume: 52 Issue: 5 Pages: 790-9
  • DOI: 10.1093/rheumatology/kes379
  • Peer Reviewed
• [Presentation] Fli1 deficiency contributes to the downregulation of endothelial protein C receptor in systemic sclerosis: a possible role in pro-thrombotic condition (2015)
  • Author(s): Saigusa R, Asano Y, Yamashita T, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Yoshizaki A, Miyagaki T, Sugaya M, Sato S.
  • Organizer: The 2015 American College of Rheumatology Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] 骨髄系細胞におけるFli1の恒常的発現低下が血管の恒常性に及ぼす影響についての検討 (2015)
  • Author(s): 谷口隆志、浅野善英、赤股要、野田真史、高橋岳浩、市村洋平、遠山哲夫、三枝良輔、吉崎歩、佐藤伸一
  • Organizer: 日本臨床免疫学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-10-22
• [Presentation] Myeloid Fli1 deficiency induces tissue fibrosis, vasculopathy, and immune abnormalities recapitulating systemic sclerosis (2014)
  • Author(s): Takashi Taniguchi, Yoshihide Asano, Kaname Akamata, Shinji Noda, Takehiro Takahashi, Yohei Ichimura, Tetsuo Toyama, Ryosuke Saigusa, Ayumi Yoshizaki, Maria Trojanowska, Shinichi Sato.
  • Organizer: The 39th Annual Meeting of the Japanease Society for Investigative Dermatology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] Fasudil ameliorates fibrosis, vasculopathy, and immune abnormalities in animal models of systemic sclerosis (2014)
  • Author(s): Tetsuo Toyama, Yoshihide Asano, Kouki Nakamura, Takashi Yamashita, Ryosuke Saigusa, Takehiro Takahashi, Yohei Ichimura, Takashi Taniguchi, Ayumi Yoshizaki, Maria Trojanowska, Shinichi Sato, Takafumi Kadono.
  • Organizer: The 39th Annual Meeting of the Japanease Society for Investigative Dermatology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2014-12-12 – 2014-12-14
• [Presentation] Am80 ameliorates bleomycin-induced dermal fibrosis by suppressing the pro-fibrotic phenotype of fibroblasts, endothelial cells, and immune cells. (2014)
  • Author(s): Tetsuo Toyama, Yoshihide Asano, Ryosuke Saigusa, Takehiro Takahashi, Yohei Ichimura, Takashi Taniguchi, Shinji Noda, Kaname Akamata, Koichi Shudo, Shinichi Sato, Takafumi Kadono.
  • Organizer: The 2014 American College of Rheumatology Annual Meeting
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-13 – 2014-11-18
• [Presentation] 強皮症と転写因子 (2014)
  • Author(s): 浅野善英
  • Organizer: 第58回日本リウマチ学会総会
  • Place of Presentation: 東京、グランドプリンスホテル新高輪 国際パミール館
  • Invited
• [Presentation] Fli1 haploinsufficiency exacerbates dermal fibrosis via activation of fibroblasts, endothelial cells and macrophages in bleomycin-treated mice. (2013)
  • Author(s): Takashi Taniguchi, Yoshihide Asano, et al.
  • Organizer: The 2013 American College of Rheumatology Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] Downregulation of KLF5 and Fli1 cooperatively contribute to distinct manifestations of systemic sclerosis in vitro and in vivo. (2013)
  • Author(s): Yoshihide Asano, et al.
  • Organizer: The 2013 American College of Rheumatology Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] 強皮症 ～線維化から考える～ (2013)
  • Author(s): 浅野善英
  • Organizer: 第112回日本皮膚科学会総会
  • Place of Presentation: 横浜、パシフィコ横浜
  • Invited