Investigation of the pathophysiologic role of inflammatory monocytes in systemic lupus erythematosus
Project/Area Number |
19K08797
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53050:Dermatology-related
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Research Institution | Nara Medical University |
Principal Investigator |
Miyagawa Fumi 奈良県立医科大学, 医学部, 講師 (00346024)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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Keywords | 全身性エリテマトーデス / インターフェロン制御因子 / 炎症性単球 / I型Iインターフェロン経路 / NF-kB経路 / 炎症性樹状細胞 / I型インターフェロン / NF-kB / 自己抗体 / 臓器障害 / SLE / I型IFN |
Outline of Research at the Start |
我々はプリスタン誘発性SLEモデルマウスを作成することで、IRF7欠損マウスでは抗核抗体の産生はみられないが、糸球体腎炎は野生型マウスと同程度に誘発されること、IRF8欠損マウスでは抗核抗体の産生、糸球体腎炎がともにみられないことを明らかにした。また野生型マウスとIRF7欠損マウスでは、プリスタン投与により腹腔内に炎症性単球の浸潤がみられるが、IRF8欠損マウスではみられないことも明らかにした。本研究では、炎症性単球が炎症性サイトカインを産生することで組織障害に関与していること、炎症性単球が組織に浸潤した後樹状細胞に変化し、自己抗原(二本鎖DNA)を認識することを明らかにする。
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Outline of Final Research Achievements |
Using a mouse model of SLE, we recently demonstrated that type I IFN pathway leads to autoantibody production whereas NF-κB activation is sufficient for the development of glomerulonephritis. Here we studied the role of IRF8 and saw that IRF8-deficient mice failed to develop either glomerulonephritis or autoantibody production. Inflammatory monocytes migrate to the peritoneal cavity in WT and IRF7-deficient mice but not in IRF8-deficient mice, and there they produce both type I IFN and proinflammatory cytokines in WT mice, while in IRF7-deficient mice they only produce proinflammatory cytokines. Furthermore, inflammatory monocytes differentiate into dendritic cells which are capable of producing proinflammatory cytokines in response to dsDNA. Collectively, type I IFN produced from inflammatory monocytes/monocyte-derived dendritic cells might be essential for autoantibody production whereas proinflammatory cytokines produced from them might mediate tissue damages in this model.
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Academic Significance and Societal Importance of the Research Achievements |
本研究では、炎症性単球および、炎症性単球が変化した樹状細胞がSLEの病態形成に関与していることを初めて明らかにした。また自己抗体の産生はI型IFN経路、臓器障害はNF-kB経路という異なるシグナル経路で制御されている可能性を示した。SLEは増悪と寛解を繰り返す自己免疫疾患で、慢性に経過し標的臓器は多岐にわたる。現在SLEに対する治療は、副作用の強いステロイド内服や免疫抑制剤が主体であり、さらなる治療法の進歩が望まれている。本研究の成果により、炎症性単球やNF-kB経路を標的にした新規治療法を確立できる可能性がある。
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Report
(4 results)
Research Products
(49 results)
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[Journal Article] Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study.2020
Author(s)
Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, Tsukasaki K; for collaborative Investigators.
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Journal Title
Cancer Sci
Volume: 111
Issue: 12
Pages: 4567-4580
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Reduced induction of human β-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by epidermal growth factor receptor monoclonal antibodies.2020
Author(s)
Ommori R, Nakamura Y, Miyagawa F, Shobatake C, Ogawa K, Koyama F, Sho M, Ota I, Kitahara T, Hontsu S, Muro S, Asada H
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Journal Title
Clin Exp Dermatol
Volume: 45
Issue: 8
Pages: 1055-1058
DOI
Related Report
Peer Reviewed
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[Journal Article] Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review.2020
Author(s)
Ogawa K, Fujimoto M, Takai T, Mitsui Y, Iwasa K, Ohsita A, Komori S, Asai J, Azukizawa H, Miyagawa F, Yurugi S, Kuwahara M, Sasaki C, Ando J, Asada H
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Journal Title
J Dermatol
Volume: 47
Issue: 7
Pages: 770-773
DOI
Related Report
Peer Reviewed
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[Presentation] Reduced induction of human b-defensins is involved in the pathological mechanism of cutaneous adverse effects caused by EGFR inhibitors2020
Author(s)
Rie Ommori, Yuki Nakamura, Fumi Miyagawa, Chinatsu Shobatake, Kohei Ogawa, Fumikazu Koyama, Masayuki Sho, Ichiro Ota, Tadashi Kitahara, Shigeto Hontsu, Sigeo Muro, Hideo Asada
Organizer
The 45th annual meeting of the Japanese Society for Investigative Dermatology
Related Report
Int'l Joint Research
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