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.
© 2022. The Author(s).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Neutralizing / pharmacology
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C-Reactive Protein / administration & dosage
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Fas Ligand Protein / genetics
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Fas Ligand Protein / immunology
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Female
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Gene Expression Regulation
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Granzymes / genetics
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Granzymes / immunology
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HMGB1 Protein / antagonists & inhibitors*
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HMGB1 Protein / genetics
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HMGB1 Protein / immunology
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Humans
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Imidazoles / pharmacology*
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Indoles / pharmacology*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle Fibers, Skeletal / drug effects*
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Muscle Fibers, Skeletal / immunology
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Muscle Fibers, Skeletal / pathology
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Muscle Strength / drug effects
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Muscle Strength / immunology
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / immunology
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Muscle, Skeletal / pathology
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Myositis / chemically induced
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Myositis / genetics
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Myositis / immunology
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Myositis / prevention & control*
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Necroptosis / drug effects*
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Necroptosis / genetics
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Necroptosis / immunology
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Perforin / genetics
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Perforin / immunology
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Polymyositis / genetics*
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Polymyositis / immunology
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Polymyositis / pathology
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Signal Transduction
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / pathology
Substances
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Antibodies, Neutralizing
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FASLG protein, human
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Fas Ligand Protein
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HMGB1 Protein
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HMGB1 protein, human
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Imidazoles
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Indoles
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PRF1 protein, human
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necrostatin-1
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Perforin
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C-Reactive Protein
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Granzymes