TY - JOUR
T1 - Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies
AU - Kamiya, Mari
AU - Mizoguchi, Fumitaka
AU - Kawahata, Kimito
AU - Wang, Dengli
AU - Nishibori, Masahiro
AU - Day, Jessica
AU - Louis, Cynthia
AU - Wicks, Ian P.
AU - Kohsaka, Hitoshi
AU - Yasuda, Shinsuke
N1 - Funding Information:
F.M. received research funding from AbbVie, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Company, Eisai, Eli Lilly and Company, ImmunoForge, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, Novartis Pharma Japan, Ono Pharmaceutical, Otsuka Pharmaceutical Factory, Pfizer, Sanofi, Takeda Pharmaceutical Company and Teijin, consulting fees from Asahi Kasei Pharma and ImmunoForge, and speaking fees from AbbVie, Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eizai, Eli Lilly and Company, Glaxo Smith Kline, Ono Pharmaceutical, and Pfizer. H.K. received consulting fees from CSL Behring and Japan Blood Products Organization. S.Y. received research funding from Abbvie, Asahi Kasei Pharma, Chugai Pharmaceutical, CSL Behring, Eisai, ImmunoForge, Mitsubishi Tanabe Pharma, and Ono pharmaceutical, speaking fees from Abbvie, Asahi Kasei Pharma, Chugai Pharmaceutical, Eisai, Eli Lilly, GlaxoSmithKline, Mitsubishi Tanabe Pharma, Ono pharmaceutical, and Pfizer. I.P.W. received consulting fees from CSL Limited. M.K., K.K., D.W., M.N., J.D., and C.L. declare that no conflict of interest exists.
Funding Information:
We thank Dr. Naoko Okiyama for providing the splenocytes of mutant OT-I mice lacking PRF1 and GZMB, Katsuko Yamasaki for the histological analysis, Dr. Naoki Kimura, Dr. Natsuka Umezawa, and Dr. Hirokazu Sasaki for obtaining muscle specimens from the patients, Dr. Shinichi Uchida for encouraging the study, Mr. Huon Wong and Ms. Jacinta Hansen for technical assistance, Dr. James Murphy, Dr. John Silke, and Dr. Jo Hildebrand for providing Ripk3−/− and Mlkl−/− mice, and Dr. Hung Nguyen for helpful discussion. This work was supported by JSPS KAKENHI Grant Number JP19K23839 (to M.K.), JP19K08903 (to F.M.) and JP15H04863 (to H.K.), Bristol-Myers Squibb Foundation grant 41907503 (to F.M.), National Health and Medical Research Council of Australia 1113577 (to I.P.W.), and John T. Reid Charitable Trusts (to I.P.W.). I.P.W. is supported by a National Health and Medical Research Council Medical Research Future Fund Practitioner Fellowship (1154325). This study was made possible through Victorian State Government Operational Infrastructure Support and the Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support scheme.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122681920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122681920&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27875-4
DO - 10.1038/s41467-021-27875-4
M3 - Article
C2 - 35013338
AN - SCOPUS:85122681920
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 166
ER -