Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies
- Author(s)
- KAMIYA, M; Mizoguchi, F; Kawahata, K; Wang, D; Nishibori, M; Day, J; Louis, C; Wicks, IP; Kohsaka, H; Yasuda, S;
- Details
- Publication Year 2022-01-10,Volume 13,Issue #1,Page 166
- Journal Title
- Nature Communications
- 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.
- Publisher
- NPG
- Research Division(s)
- Inflammation
- PubMed ID
- 35013338
- Publisher's Version
- https://doi.org/10.1038/s41467-021-27875-4
- Open Access at Publisher's Site
https://doi.org/ 10.1038/s41467-021-27875-4- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-02-18 11:36:39
Last Modified: 2022-02-18 01:20:14