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
  • 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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