A Fundamental Study on the Immunopathogenic Role of Pulmonary Macrophages Toward the Development of Novel Therapies for Fulminant Interstitial Pneumonia

• Project/Area Number: 22K08526
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Arima Masafumi 獨協医科大学, 医学部, 教授 (00202763)
• Co-Investigator(Kenkyū-buntansha): 倉沢 和宏 獨協医科大学, 医学部, 特任教授 (30282479) ; 大和田 高義 獨協医科大学, 医学部, 講師 (30456016) ; 田中 彩絵 獨協医科大学, 医学部, 助教 (30743067)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2024: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 間質性肺炎 / マクロファージ

Outline of Research at the Start

重症の急速進行性間質性肺炎（RP-ILD）の共通病態にはマクロファージ活性化症候群に類似した様々な免疫系細胞の異常活性化が深く関与すると考えられるが，その発症と増悪機序は不明である．本研究は自己免疫疾患やウイルス感染症に合併する重症難治化のILDや肺血管炎および肺胞出血など劇症型肺炎に共通する病理メカニズムの解明するために遺伝子改変マウスを用いた疾患モデルの解析を中心とした基盤研究を行う．そして，劇症型肺炎の病態に重要な役割を果たすと考えられる単球・マクロファージによる病態制御機構の解明と新規の根治的治療法の開発を目指す．

Outline of Final Research Achievements

Interstitial lung disease (ILD) associated with collagen vascular diseases is a critical complication in terms of life prognosis.A common pathological mechanism underlying severe forms of ILD is thought to involve aberrant activation of various immune cells resembling macrophage activation syndrome (MAS).This study aimed to elucidate the pathological significance of lung macrophages and the functional role of the double-stranded RNA-editing enzyme ADAR1 as a shared mechanism in fulminant ILD, including refractory and rapidly progressive types.Using wild-type (WT) mice and macrophage-specific Adar1-deficient mice (Lys-Adar1-cKO), we analyzed a model of refractoryautoimmune fulminant interstitial pneumonia.Our analysis revealed that lung macrophages are involved in the pathogenesis of ILD, and that activation of lung macrophages due to impaired ADAR1 function plays a critical role in the exacerbation of ILD.

Academic Significance and Societal Importance of the Research Achievements

本研究では，研究代表者が独自に樹立したマクロファージ特異的Adar1欠損マウス（Lys-Adar1-cKO）を用いた自己免疫性ILDモデルを解析し，劇症型ILDに共通する基盤的な病態メカニズムの解明に向けた探索的研究を行った．その結果，肺マクロファージを中心とする過剰な免疫応答の中で，ADAR1の機能的役割を初めて明らかにすることができた．今後，本研究成果を起点として，劇症型ILDの難治化に共通する新たな病態概念が見出されることが期待される．さらに，本研究の成果は，劇症型ILDに対する根治的治療法の開発へ応用される可能性も有しており，社会的にも大きな意義を持つと考えられる．

Research Products

• [Journal Article] Clinical features and risk factors of flare in anti-synthetase syndrome (2025)
  • Author(s): Hasegawa Anna、Kurasawa Kazuhiro、Koike Ryota、Sato Rika、Kikuchi Azusa、Komatsu Sara、Sakaue Yusuke、Aizawa Yuki、Shimizu Aya、Yoshida Yuhi、Hiyama Tomoka、Miyao Tomoyuki、Tanaka Ayae、Arai Satoko、Maezawa Reika、Arima Masafumi、Ikeda Kei
  • Journal Title: Clinical Rheumatology Volume: - Issue: 6 Pages: 2431-2438
  • DOI: 10.1007/s10067-025-07398-9
  • Peer Reviewed
• [Journal Article] Pulmonary and serum cytokine profiles of patients with anti-ARS and anti-MDA5 antibodies (2025)
  • Author(s): Kurasawa Kazuhiro、Arai Satoko、Taniguchi-Namiki Yumeko、Komatsu Sara、Shimizu Aya、Hasegawa Anna、Hiyama Tomoka、Miyao Tomoyuki、Tanaka Ayae、Owada Takayoshi、Hirata Hirokuni、Fukushima Yasutsugu、Arima Masafumi、Maezawa Reika、Ikeda Kei
  • Journal Title: Journal of Autoimmunity Volume: 151 Pages: 103374-103374
  • DOI: 10.1016/j.jaut.2025.103374
  • Peer Reviewed
• [Journal Article] Identifying two pathways to poor prognosis in patients with anti-MDA5 antibodies: insights from prognostic factor and cytokines analysis (2025)
  • Author(s): Shimizu Aya、Kurasawa Kazuhiro、Hiyama Tomoka、Komatsu Sara、Kikuchi Azusa、Yoshida Yuhi、Hasegawa Anna、Miyao Tomoyuki、Tanaka Ayae、Arai Satoko、Maezawa Reika、Arima Masafumi、Ikeda Kei
  • Journal Title: Arthritis Research & Therapy Volume: 27 Issue: 1
  • DOI: 10.1186/s13075-025-03558-z
  • Peer Reviewed
• [Journal Article] Differences and similarities in cytokine profiles of macrophage activation syndrome in systemic lupus erythematosus and adult-onset Still’s disease (2023)
  • Author(s): Hiyama Tomoka、Kurasawa Kazuhiro、Hasegawa Anna、Miyao Tomoyuki、Tanaka Ayae、Arai Satoko、Arima Masafumi、Maezawa Reika
  • Journal Title: Clinical and Experimental Medicine Volume: 23 Issue: 7 Pages: 3407-3416
  • DOI: 10.1007/s10238-023-00988-4
• [Journal Article] Changing patterns of pulmonary abnormalities in rheumatoid arthritis (2023)
  • Author(s): Tanaka Ayae、Kurasawa Kazuhiro、Soda Sayo、Takamura Yuta、Miyao Tomoyuki、Hasegawa Anna、Hiyama Tomoka、Yamazaki Ryutaro、Arai Satoko、Owada Takayoshi、Arima Masafumi、Arakawa Hiroaki、Maezawa Reika
  • Journal Title: Respiratory Investigation Volume: 61 Issue: 1 Pages: 27-39
  • DOI: 10.1016/j.resinv.2022.09.002
• [Presentation] 二本鎖RNA編集酵素ADAR1のマクロファージ特異的欠損マウスは抗MDA5抗体陽性の劇症型肺炎を発症する (2024)
  • Author(s): 田中彩絵, 大和田 高義, 小松 紗良, 長谷川 杏奈, 前澤 玲華, 平田 博国, 福島 康次, 倉沢 和宏, 池田 啓, 有馬 雅史
  • Organizer: 第68回日本リウマチ学会総会・学術集会
• [Presentation] ADAR1 in bronchial epithelial cells is involved in the airway mucosal immune system in a mouse model of asthma (2022)
  • Author(s): 田中彩絵
  • Organizer: 日本免疫学会
  • Int'l Joint Research