A new therapeutic strategy against systemic sclerosis targeting skin immunity

• Project/Area Number: 21K19473
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: ASANO YOSHIHIDE 東北大学, 医学系研究科, 教授 (60313029)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 全身性強皮症 / 皮膚免疫 / 制御性T細胞 / 核酸医薬 / 臓器線維化 / 真皮樹状細胞 / 臓器連関

Outline of Research at the Start

皮膚にRaldh1 siRNAを投与し、皮膚におけるiTregの誘導を選択的に抑制したBLM誘発強皮症モデルを作製する。このモデルにおいて、肺・食道・唾液腺の線維化の程度について検討する。次に、皮膚所属リンパ節由来DCを用いて、RALDH1の発現制御に関連するmicroRNAの同定を試みる。microRNAが同定できたら、BLM誘発強皮症モデルマウスの皮膚にそれらを投与し、臓器線維化が抑制されるか否かを検討する。また、臨床応用への一歩として、microneedleによるmicroRNAのマウス皮膚への投与を試みる。

Outline of Final Research Achievements

The etiology of systemic sclerosis (SSc) still remains unknown, but we hypothesized that skin immunity may regulate multi-organ fibrosis based on the following facts: organ fibrosis begins in the skin and the skin is the largest immune organ of the human body in contact with the outside world. Our previous study suggested that RALDH1 activity of dermal DCs in SSc lesional skin is decreased and induction of iTregs is suppressed. The present study showed that suppression of RALDH1 expression in the skin of BLM-treated mice increased fibrosis not only in the skin but also in the lungs　and esophagus. These results suggest that RALDH1 activity in the skin regulates skin stiffness in SSc and may also regulate pulmonary and esophageal fibrosis. We are currently working to identify microRNAs that induce RALDH1 expression.

Academic Significance and Societal Importance of the Research Achievements

近年、アレルギー疾患においては皮膚免疫の重要性が示されており、アトピー性皮膚炎が喘息や花粉症、食物アレルギーの発症につながるアレルギーマーチという概念が確立されている。本研究成果は、全身性強皮症に代表される膠原病においても皮膚免疫が多臓器障害を制御している可能性を示唆している。申請者は既に全身性エリテマトーデスにおいて皮膚免疫がその発症に深く関わることを明らかにしているが、これらの研究成果は皮膚免疫が全身性免疫疾患の治療戦略の標的となり得ることを示唆している。皮膚は外用薬や貼付薬で容易にアクセス可能であり、新規治療薬開発の観点からも学術的・社会的意義の高い研究成果である。

Research Products

• [Journal Article] Native T1 mapping in early diffuse and limited systemic sclerosis, and its association with diastolic function. (2023)
  • Author(s): Purevsuren M, Uehara M, Ishizuka M, Suzuki Y, Shimbo M, Kakuda N, Ishii S, Sumida H, Miyazaki M, Yamashita T, Yoshizaki A, Asano Y, Sato S, Hatano M, Komuro I.
  • Journal Title: J Cardiol. Volume: - Issue: 2 Pages: 100-107
  • DOI: 10.1016/j.jjcc.2023.03.003
  • Peer Reviewed
• [Journal Article] Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs. (2023)
  • Author(s): Wang W, Bale S, Wei J, Yalavarthi B, Bhattacharyya D, Yan JJ, Abdala-Valencia H, Xu D, Sun H, Marangoni RG, Herzog E, Berdnikovs S, Miller SD, Sawalha AH, Tsou PS, Awaji K, Yamashita T, Sato S, Asano Y, Tiruppathi C, Yeldandi A, Schock BC, Bhattacharyya S, Varga J.
  • Journal Title: Nat Commun. Volume: 14 Issue: 1 Pages: 523-523
  • DOI: 10.1038/s41467-022-33767-y
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic effect of cyclin-dependent kinase 4/6 inhibitor on dermal fibrosis in murine models of systemic sclerosis. (2022)
  • Author(s): Yamamoto A, Saito T, Hosoya T, Kawahata K, Asano Y, Sato S, Mizoguchi F, Yasuda S, Kohsaka H.
  • Journal Title: Arthritis and rheumatology(Hoboken,N.J.) Volume: 74 Issue: 5 Pages: 860-870
  • DOI: 10.1002/art.42042
  • Peer Reviewed
• [Journal Article] The Contribution of LIGHT (TNFSF14) to the Development of Systemic Sclerosis by Modulating IL-6 and T Helper Type 1 Chemokine Expression in Dermal Fibroblasts. (2022)
  • Author(s): Ikawa T, Ichimura Y, Miyagawa T, Fukui Y, Toyama S, Omatsu J, Awaji K, Norimatsu Y, Watanabe Y, Yoshizaki A, Sato S, Asano Y.
  • Journal Title: J Invest Dermatol. Volume: 142 Issue: 6 Pages: 1541-1551
  • DOI: 10.1016/j.jid.2021.10.028
  • Peer Reviewed
• [Journal Article] Percentage of residual B cells after 2 weeks of rituximab treatment predicts the improvement of systemic sclerosis‐associated interstitial lung disease (2021)
  • Author(s): Ebata Satoshi、Yoshizaki Ayumi、Fukasawa Takemichi、Yoshizaki‐Ogawa Asako、Asano Yoshihide、Kashiwabara Kosuke、Oba Koji、Sato Shinichi
  • Journal Title: The Journal of Dermatology Volume: 49 Issue: 1 Pages: 179-183
  • DOI: 10.1111/1346-8138.16206
  • Peer Reviewed
• [Journal Article] Fli1 deficiency suppresses RALDH1 activity of dermal dendritic cells and related induction of regulatory T cells: a possible role in scleroderma (2021)
  • Author(s): Miura Shunsuke、Watanabe Yusuke、Saigusa Ryosuke、Yamashita Takashi、Nakamura Kouki、Hirabayashi Megumi、Miyagawa Takuya、Yoshizaki Ayumi、Trojanowska Maria、Sato Shinichi、Asano Yoshihide
  • Journal Title: Arthritis Research & Therapy Volume: 23 Issue: 1 Pages: 137-137
  • DOI: 10.1186/s13075-021-02520-z
  • Peer Reviewed / Open Access
• [Presentation] 会頭特別企画１ Dermatropic/trophic 他科領域と繋がる皮膚科研究 皮膚と他臓器病変をつなぐ：全身性強皮症 (2021)
  • Author(s): 浅野善英
  • Organizer: 第120回日本皮膚科学会総会
  • Invited