2. Academic Validation
  3. 4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway

4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway

  • Int Immunopharmacol. 2023 Mar 31;118:110104. doi: 10.1016/j.intimp.2023.110104.
Yu-Tong Wu 1,  Wen-Ting Xu 1,  Li Zheng 1,  Sheng Wang 2,  Juan Wei 2,  Mei-Yun Liu 2,  Huan-Ping Zhou 2,  Quan-Fu Li 2,  Xuan Shi 3,  Xin Lv 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Fuyang Hospital of Anhui Medical University, Anhui Medical University, Fuyang, Anhui, China; Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3 Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: [email protected].
  • 4 Department of Anesthesiology, Fuyang Hospital of Anhui Medical University, Anhui Medical University, Fuyang, Anhui, China; Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: [email protected].
PMID: 37004345 DOI: 10.1016/j.intimp.2023.110104
Abstract

Acute respiratory distress syndrome (ARDS) is a high-mortality pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. As of yet, there is no proven effective therapy for ARDS. Itaconate, an immunomodulatory derivative accumulated during inflammatory macrophage activation, has attracted widespread attention for its potent anti-inflammatory and anti-oxidative properties. This study pointed to explore the protective impacts of 4-octyl itaconate (4-OI) on ARDS. The results showed that lung injury was attenuated markedly after 4-OI pre-treatment, as represented by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors. LPS stimulation induced NLRP3-mediated Pyroptosis in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), IL-18 and IL-1β release, and these changes could be prevented by 4-OI pretreatment. Mechanistically, 4-OI eliminated mitochondrial Reactive Oxygen Species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP) in alveolar macrophages (AMs) under oxidative stress. In addition, 4-OI pretreatment markedly downregulated Cyclic GMP-AMP Synthase (cGAS), stimulator of interferon genes (STING) expression, and interferon regulatory factor 3 (IRF3) phosphorylation in vitro and in vivo. Meanwhile, inhibition of STING/IRF3 pathway alleviated NLRP3-mediated Pyroptosis induced by LPS in vitro. Taken together, this study indicated that 4-OI ameliorated ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage Pyroptosis in a STING/IRF3-dependent manner, which further revealed the potential mechanism of itaconate in preventing inflammatory diseases.

Keywords

4-octyl itaconate; Acute respiratory distress syndrome; Macrophage pyroptosis; Mitochondrial dysfunction; NLRP3 inflammasome; cGAS/STING pathway.

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