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

• Published in: Chinese journal of natural medicines Vol. 22; no. 5; pp. 402 - 415
• Main Authors: XIU, Ye, WANG, Sihao, ZHANG, Ping, LI, Chengwei, WU, Zhixin, WEN, Jincai, XU, Yingjie, LV, Guiji, ZHAO, Xiaomei, DONG, Xu, CHEN, Yichong, LI, Junjie, WANG, Yan, ZOU, Liang, XIAO, Xiaohe, BAI, Zhaofang
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.05.2024
• Subjects: Animals; cGAS-STING pathway; Glucosides - pharmacology; Humans; Inflammation; Interferon Regulatory Factor-3 - metabolism; LPS/D-GalN; Macrophages - drug effects; Macrophages - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Paeonia - chemistry; Signal Transduction - drug effects; STING inhibitor; THP-1 Cells; Total glucosides of gaeony; LPS/D-GalN; Inflammation; STING inhibitor; Total glucosides of gaeony; cGAS-STING pathway
• ISSN: 1875-5364; 1875-5364
• DOI: 10.1016/S1875-5364(24)60572-8

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.