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Roles of programmed death-1 and muscle innate lymphoid cell-derived interleukin 13 in sepsis-induced intensive care unit-acquired weakness.
Akama, Yuichi; Park, Eun Jeong; Satoh-Takayama, Naoko; Ito, Atsushi; Kawamoto, Eiji; Gaowa, Arong; Matsuo, Eri; Oikawa, Satoshi; Saito, Masafumi; Inoue, Shigeaki; Akimoto, Takayuki; Suzuki, Kei; Shimaoka, Motomu.
Afiliação
  • Akama Y; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Park EJ; Department of Emergency and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Japan.
  • Satoh-Takayama N; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Ito A; Precision Immune Regulation RIKEN Research Unit, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
  • Kawamoto E; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Gaowa A; Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan.
  • Matsuo E; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Oikawa S; Department of Emergency and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Japan.
  • Saito M; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Inoue S; Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Akimoto T; Faculty of Sport Sciences, Waseda University, Saitama, Japan.
  • Suzuki K; Department of Disaster and Emergency and Critical Care Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
  • Shimaoka M; Department of Emergency and Critical Care Medicine, Wakayama Medical University, Wakayama, Japan.
Article em En | MEDLINE | ID: mdl-39016179
ABSTRACT

BACKGROUND:

Intensive care unit-acquired weakness (ICU-AW) is a syndrome characterized by a long-term muscle weakness often observed in sepsis-surviving patients during the chronic phase. Although ICU-AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death-1 (PD-1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU-AW remains to be elucidated. Here, we study how PD-1 deficiency affects sepsis-induced skeletal muscle dysfunction in a preclinical sepsis model.

METHODS:

Chronic sepsis model was developed by treating wild-type (WT) and PD-1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15-17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL-13) and PD-1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow-twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL-13 followed by gene expression measurements.

RESULTS:

WT septic mice exhibited decreased muscle weight (quadriceps, P < 0.01; gastrocnemius, P < 0.05; and tibialis anterior, P < 0.01) and long-term muscle weakness (P < 0.0001), whereas PD-1 KO septic mice did not exhibit any reduction in muscle weights and strengths. Slow-twitch specific mRNAs, including myoglobin (Mb), troponin I type 1 (Tnni1), and myosin heavy chain 7 (Myh7) were decreased in WT skeletal muscle (Mb, P < 0.0001; Tnni1, P < 0.05; and Myh7, P < 0.05) after sepsis induction, but mRNA expressions of Tnni1 and Myh7 were increased in PD-1 KO septic mice (Mb, not significant; Tnni1, P < 0.0001; and Myh7, P < 0.05). Treatment of C2C12 myotube cells with LPS decreased the expression of slow-twitch mRNAs, which was restored by IL-13 (Mb, P < 0.0001; Tnni1, P < 0.001; and Myh7, P < 0.05). IL-13 production was significantly higher in ILC2s compared to T cells in skeletal muscle (P < 0.05). IL-13-producing ILC2s in skeletal muscle were examined and found to increase in PD-1 KO septic mice, compared with WT septic mice (P < 0.05). ILC2-derived IL-13 was increased by PD-1 KO septic mice and thought to protect the muscles from experimental ICU-AW.

CONCLUSIONS:

Long-term muscle weakness in experimental ICU-AW was ameliorated in PD-1 KO mice. ILC2-derived IL-13 production in skeletal muscles was increased in PD-1 KO mice, thereby suggesting that IL-13 alleviates muscle weakness during sepsis. This study demonstrates the effects of PD-1 blockade in preserving muscle strength during sepsis through an increase in ILC2-derived IL-13 and may be an attractive therapeutic target for sepsis-induced ICU-AW.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: J Cachexia Sarcopenia Muscle Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: J Cachexia Sarcopenia Muscle Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Japão País de publicação: Alemanha