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

by Selleckchem | Apr 28 2023

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.

Comments：

The study aimed to investigate the therapeutic potential of 4-octyl itaconate (4-OI) on acute respiratory distress syndrome (ARDS), a pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. The results of the study showed that pretreatment with 4-OI significantly attenuated lung injury in ARDS, as evidenced by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors.

The study also found that LPS stimulation induced NLRP3-mediated pyroptosis both in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), release of IL-18 and IL-1β, which could be prevented by 4-OI pretreatment. The authors further revealed that the protective effect of 4-OI was mediated through the inhibition of the STING/IRF3 pathway, which downregulated cGAS expression, STING expression, and IRF3 phosphorylation in vitro and in vivo.

Moreover, the authors showed that 4-OI rescued mitochondrial dysfunction and inhibited NLRP3-mediated macrophage pyroptosis in alveolar macrophages (AMs) under oxidative stress by eliminating mitochondrial reactive oxygen species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP).

Overall, the study provides evidence for the potential therapeutic application of 4-OI in ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage pyroptosis in a STING/IRF3-dependent manner. These findings shed light on the potential mechanism of itaconate in preventing inflammatory diseases. However, further research is needed to determine the clinical significance of these findings and to investigate the safety and efficacy of 4-OI in ARDS patients.