Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies.
Mari KamiyaFumitaka MizoguchiKimito KawahataDengli WangMasahiro NishiboriJessica A DayCynthia LouisIan P WicksHitoshi KohsakaShinsuke YasudaPublished in: Nature communications (2022)
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.
Keyphrases
- cell death
- cell cycle arrest
- skeletal muscle
- oxidative stress
- interstitial lung disease
- induced apoptosis
- endothelial cells
- end stage renal disease
- high glucose
- chronic kidney disease
- signaling pathway
- diabetic rats
- endoplasmic reticulum stress
- ejection fraction
- peritoneal dialysis
- mouse model
- combination therapy
- peripheral blood