2. Academic Validation
  3. TrxR1 is involved in the activation of Caspase-11 by regulating the oxidative-reductive status of Trx-1

TrxR1 is involved in the activation of Caspase-11 by regulating the oxidative-reductive status of Trx-1

  • Redox Biol. 2024 Sep:75:103277. doi: 10.1016/j.redox.2024.103277.
Dongsheng Bai 1,  Chen Zhou 1,  Jiaying Du 1,  Jiawei Zhao 1,  Chunyang Gu 1,  YuXiang Wang 1,  Lulu Zhang 2,  Na Lu 3,  Yue Zhao 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
  • 2 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China. Electronic address: lulu_0219@njmu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. Electronic address: nalu@cpu.edu.cn.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. Electronic address: yuezhao@cpu.edu.cn.
PMID: 39059206 DOI: 10.1016/j.redox.2024.103277
Abstract

Sepsis is a common complication of infections that significantly impacts the survival of critically patients. Currently, effective pharmacological treatment strategies are lacking. Auranofin, known as an inhibitor of Thioredoxin reductase (TrxR), exhibits anti-inflammatory activity, but its role in sepsis is not well understood. Here, we demonstrate the significant inhibitory effect of Auranofin on sepsis in a cecal ligation and puncture (CLP) mouse model. In vitro, Auranofin inhibits Pyroptosis triggered by Caspase-11 activation. Further investigations reveal that inhibiting TrxR1 suppresses macrophage Pyroptosis induced by E. coli, while TrxR2 does not exhibit this effect. TrxR1, functioning as a reductase, regulates the oxidative-reductive status of Thioredoxin-1 (Trx-1). Mechanistically, the modulation of Trx-1's reductive activity by TrxR1 may be involved in Caspase-11 activation-induced Pyroptosis. Additionally, inhibiting TrxR1 maintains Trx-1 in its oxidized state. The oxidized form of Trx-1 interacts with Caveolin-1 (CAV1), regulating outer membrane vesicle (OMV) internalization. In summary, our study suggests that inhibiting TrxR1 suppresses OMV internalization by maintaining the oxidized form of Trx-1, thereby restricting Caspase-11 activation and alleviating sepsis.

Keywords

Caspase-11; Caveolin-1; Outer membrane vesicle; Thioredoxin-1; TrxR.

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