1. Academic Validation
  2. Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

  • Nat Commun. 2022 Jan 10;13(1):166. doi: 10.1038/s41467-021-27875-4.
Mari Kamiya 1 Fumitaka Mizoguchi 1 Kimito Kawahata 1 2 Dengli Wang 3 Masahiro Nishibori 3 Jessica Day 4 Cynthia Louis 4 Ian P Wicks 4 Hitoshi Kohsaka 1 5 Shinsuke Yasuda 6
Affiliations

Affiliations

  • 1 Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan.
  • 2 Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, 216-8511, Japan.
  • 3 Department of Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, 700-8558, Japan.
  • 4 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
  • 5 Chiba-Nishi General Hospital, Matsudo, Chiba, 270-2251, Japan.
  • 6 Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8519, Japan. [email protected].
Abstract

Muscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent Necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent Apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of Necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. 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 polymyositis providing an alternative to current therapies directed at leukocytes.

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