Objective: To investigate the potential of Salvia miltiorrhiza water extract (SMWE) as a modulator of the cGAS-STING signaling pathway, which is implicated in the pathogenesis of immune and inflammatory disorders, and to elucidate its underlying mechanism of action through in vitro and in vivo experiments. Methods: The cGAS-STING signaling pathway was activated in bone marrow-derived macrophages (BMDMs), Tohoku hospital pediatrics-1 (THP-1) cells, and peripheral blood mononuclear cells (PBMCs). The effect of SMWE on the expression of phosphorylated interferon regulatory factor 3 (IRF3) and phosphorylated STING after aberrant activation of the cGAS-STING pathway was detected by immunoblotting. Subsequently, real-time quantitative PCR was performed to detect changes in the mRNA levels of interferon type I (IFN), interferon-stimulated genes and inflammatory factors. The effect of SMWE on STING oligomerisation and the interaction between STING, Tank Binding Kinase 1 (TBK1) and IRF3 was investigated by immunoblotting. A model of acute liver injury (ALI) caused by lipopolysaccharide/D-galactosamine (LPS/D-GaIN) was used to test the effects of SMWE on inflammation mediated by the cGAS-STING signaling cascade. Results: SMWE significantly inhibited the phosphorylation of STING and IRF3, thereby suppressing the activation of the cGAS-STING signaling pathway. It also stopped the cGAS-STING pathway from working by stopping the production of type I interferons and interferon-stimulated genes, like interferon-stimulated gene 15 (ISG15) and C-X-C motif chemokine ligand 10 (CXCL10). SMWE also reduced the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). SMWE also significantly improved ALI resulting from LPS/D-GaIN by diminishing the hyperactivation of the cGAS-STING signalling pathway. Mechanistic analysis revealed that SMWE disrupted the interaction between STING and TBK1. Conclusion: SMWE is a potent modulator of aberrant activation of the cGAS-STING pathway and is able to prevent and treat LPS/D-GaIN-induced ALI by inhibiting activation of the cGAS-STING pathway.
关键词:
急性肝损伤;cGAS-STING;IFN-β;丹参;STING
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Project Supported:
This study is funded by Project supported by the Natural Science Foundation of Beijing, China (No. 7232321) and the National Natural Science Foundation of China under the Joint Fund Key Project (No. U23A20519).
