The role of extracellular ATP in the pathogenesis of skin sclerosis and vasculopathy in systemic sclerosis

• Project/Area Number: 17K10205
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Gunma University
• Principal Investigator: Ishikawa Osamu 群馬大学, 大学院医学系研究科, 教授 (90168188)
• Co-Investigator(Kenkyū-buntansha): 茂木 精一郎 群馬大学, 大学院医学系研究科, 准教授 (20420185)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 全身性強皮症 / 皮膚硬化 / 細胞外ATP / 線維化 / ATP / 治療 / 強皮症 / 膠原病

Outline of Final Research Achievements

We identified that hypoxia in the tissues caused by vascular damage induces the release of extracellular ATP from vascular endothelial cells and fibroblasts, and the released extracellular ATP binds to P2Y2 receptors on fibroblasts, causing increased IL-6 production, increased proliferative capacity, and increased type I collagen production via tyrosine phosphorylation of p38. These results suggest that extracellular ATP might be involved in the mechanism of skin fibrosis in systemic sclerosis.The inhibition of ATP-induced IL-6 and type 1 collagen production by the inhibitor of P2Y2 receptor suggested that P2Y2 receptor inhibitor could be potentially applied in the treatment of fibrosis in systemic sclerosis.

Academic Significance and Societal Importance of the Research Achievements

我々は、細胞外ATPが強皮症の血管障害と皮膚の線維化（硬化）の機序において重要な役割を果たすことを明らかにした。また、P2Y2受容体阻害剤が強皮症の線維化の治療に応用できる可能性が示唆された。本研究の成果は強皮症の２つの主要病態である血管障害と線維化の病態における細胞外ATPの役割を明らかにすることにつながり、２つの主要病態を改善することができる革新的な治療法に応用できる可能性が示唆される。

Research Products

• [Journal Article] The Regulation of Skin Fibrosis in Systemic Sclerosis by Extracellular ATP via P2Y2 Purinergic Receptor. (2019)
  • Author(s): Perera LMB, Sekiguchi A, Uchiyama A, Uehara A, Fujiwara C, Yamazaki S, Yokoyama Y, Ogino S, Torii R, Hosoi M, Ishikawa O, Motegi S
  • Journal Title: Journal of Investigative Dermatology Volume: 139 Pages: 890-899
  • Peer Reviewed
• [Presentation] Mechanistic insight into the extracellular ATP-induced IL-6 via purinergic receptor in systemic sclerosis dermal fibroblasts (2017)
  • Author(s): Buddhini Perera, Akihiko Uchiyama, Akiko Sekiguchi, Chisako Fujwara, Osamu Ishikawa, Sei-ichiro Motegi
  • Organizer: 2017 Society for Investigative Dermatology Annual Meeting
  • Int'l Joint Research
• [Presentation] The regulation of skin fibrosis in systemic sclerosis by extracellular ATP via P2Y2 purinergic receptor (2017)
  • Author(s): Buddhini Perera, Akiko Sekiguchi, Akihiko Uchiyama, Akihito Uehara, Chisako Fujwara, Sahori Yamazaki, Osamu Ishikawa, Sei-ichiro Motegi
  • Organizer: The 42nd annual meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research