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

Apr 2, 2023International immunopharmacology

4-Octyl Itaconate reduces lung immune cell death in ARDS by improving mitochondrial function and lowering cGAS/STING pathway activation

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Abstract

Pre-treatment with 4-octyl itaconate significantly reduced lung injury in models of acute respiratory distress syndrome.

Lung injury was marked by decreased pulmonary edema, reduced inflammatory cell infiltration, and lower production of inflammatory factors after 4-OI treatment.
LPS stimulation triggered NLRP3-mediated pyroptosis, evidenced by the cleavage of gasdermin D and release of IL-18 and IL-1β, which 4-OI pretreatment prevented.
4-OI treatment reduced mitochondrial reactive oxygen species and mtDNA leakage in alveolar macrophages under oxidative stress.
Cyclic GMP-AMP synthase, STING expression, and phosphorylated interferon regulatory factor 3 levels were significantly downregulated by 4-OI.
Inhibition of the STING/IRF3 pathway lessened LPS-induced NLRP3-mediated pyroptosis in vitro.

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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.

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

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