Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction

内部收益率3 阻塞(统计) 医学 计算机科学 内科学 物理 受体 计算机网络 热力学 先天免疫系统
作者
Xiu Ye,Sihao WANG,Ping Zhang,Chengwei Li,Zhixin Wu,Jincai Wen,Yingjie Xu,Gui-Ji Lv,Xiaomei ZHAO,Dong Xu,Yichong CHEN,Junjie Li,Yan Wang,Liang Zou,Xiaohe Xiao,Zhaofang Bai
出处
期刊:Chinese Journal of Natural Medicines [Elsevier]
卷期号:22 (5): 402-415 被引量:1
标识
DOI:10.1016/s1875-5364(24)60572-8
摘要

In the realm of autoimmune and inflammatory diseases, the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway has been thoroughly investigated and established. Despite this, the clinical approval of drugs targeting the cGAS-STING pathway has been limited. The Total glucosides of paeony (TGP) is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis (RA), emerged as a subject of our study. We found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway, triggered by various cGAS-STING agonists, in mouse bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) cells. This inhibition was noted alongside the suppression of interferon regulatory factor 3 (IRF3) phosphorylation and the expression of interferon-beta (IFN-β), C-X-C motif chemokine ligand 10 (CXCL10), and inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The mechanism of action appeared to involve the TGP's attenuation of the STING-IRF3 interaction, without affecting STING oligomerization, thereby inhibiting the activation of downstream signaling pathways. In vivo, the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid (DMXAA) and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway, offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway.
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