Pathophysiology of inflammatory myopathies in the light of immune response and muscle disfunction induced by injured muscle fibers

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17422
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kamiya Mari 東京医科歯科大学, 医学部附属病院, 助教 (20844377)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 炎症性筋疾患 / 細胞死 / ネクロトーシス / HMGB1

Outline of Final Research Achievements

Polymyositis is a chronic inflammatory myopathy, which affects proximal muscles leading to progressive and persistent disability.
Here, we showed that the pattern of cell death of muscle fibers inflammatory myopathies is necroptosis using human muscle biopsy specimens of PM patients and models of PM in vitro and in vivo. The Inhibition of necroptosis suppresses not only muscle fiber death but also the release of inflammatory molecules including HMGB1, one of damage associated molecular patterns (DAMPs). Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating PM providing an alternative to current therapies directed at leukocytes.

Free Research Field

膠原病・リウマチ内科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、炎症性筋疾患において、免疫細胞からの傷害を受けた筋細胞がネクロトーシスに至り、HMGB1などの炎症介在因子の放出を介して炎症や筋機能障害を更に悪化させることを明らかにしました。この発見により、従来は免疫細胞の単なる標的と考えられていた筋細胞が、ネクロトーシスを介して病態を増悪させる攻撃者として機能することが示されました。筋細胞の細胞死や、それに伴い放出される炎症介在因子を標的とした治療は、ステロイドや免疫抑制剤のように免疫細胞を非特異的に抑制するものではないため、感染症などの副作用が少なく、これらの標準治療で効果不十分な症例への効果も期待できる、有望な治療法である可能性があります。