Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

Mari Kamiya, Fumitaka Mizoguchi, Kimito Kawahata, Dengli Wang, Masahiro Nishibori, Jessica Day, Cynthia Louis, Ian P. Wicks, Hitoshi Kohsaka, Shinsuke Yasuda

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number166
JournalNature communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint

Dive into the research topics of 'Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies'. Together they form a unique fingerprint.

Cite this