Glabridin improves autoimmune disease in Trex1-deficient mice by reducing type I interferon production

  • Mol Med. 2023 Dec 8;29(1):167. doi: 10.1186/s10020-023-00754-y.
Jincai Wen  #  1  2  3 ,  Wenqing Mu  #  1  4  2 ,  Hui Li  #  1  2 ,  Yulu Yan  5 ,  Xiaoyan Zhan  1  2  3 ,  Wei Luo  1  2 ,  Zhongxia Wang  6 ,  Wen Kan  1  2 ,  Jia Zhao  1  2 ,  Siwen Hui  1  2 ,  Ping He  1  2 ,  Shuanglin Qin  7 ,  Yingjie Xu  1  2 ,  Ping Zhang  8 ,  Xiaohe Xiao  9  10  11 ,  Guang Xu  12 ,  Zhaofang Bai  13  14  15
Affiliations
  • 1. Department of Hepatology, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China.
  • 2. Fifth Medical Center of Chinese, China Military Institute of Chinese Materia, PLA General Hospital, Beijing, 100039, China.
  • 3. National Key Laboratory of Kidney Diseases, Beijing, 100005, China.
  • 4. State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, 215123, Jiangsu, China.
  • 5. Ningde Hospital of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, China.
  • 6. Nutrition Department of the Fifth Medical Center of the PLA General Hospital, Beijing, 100039, China.
  • 7. School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, People's Republic of China.
  • 8. Department of Pharmacy, Medical Supplies Center of PLA General Hospital, Beijing, 100039, China.
  • 9. Department of Hepatology, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China. [email protected].
  • 10. Fifth Medical Center of Chinese, China Military Institute of Chinese Materia, PLA General Hospital, Beijing, 100039, China. [email protected].
  • 11. National Key Laboratory of Kidney Diseases, Beijing, 100005, China. [email protected].
  • 12. School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China. [email protected].
  • 13. Department of Hepatology, The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, 100039, China. [email protected].
  • 14. Fifth Medical Center of Chinese, China Military Institute of Chinese Materia, PLA General Hospital, Beijing, 100039, China. [email protected].
  • 15. National Key Laboratory of Kidney Diseases, Beijing, 100005, China. [email protected].
  • # Contributed equally.
PMID: 38066431 DOI: 10.1186/s10020-023-00754-y
Abstract

Background: The cGAS-STING signaling pathway is an essential section of the natural immune system. In recent years, an increasing number of studies have shown a strong link between abnormal activation of the cGAS-STING signaling pathway, a natural immune pathway mediated by the nucleic acid receptor cGAS, and the development and progression of autoimmune diseases. Therefore, it is important to identify an effective compound to specifically downregulate this pathway for disease.

Methods: The effect of Glabridin (Glab) was investigated in BMDMs and Peripheral blood mononuclear cell (PBMC) by establishing an in vitro model of cGAS-STING signaling pathway activation. An activation model stimulated by DMXAA was also established in mice to study the effect of Glab. On the Other hand, we investigated the possible mechanism of action of Glab and the effect of Glab on Trex1-deficient mice.

Results: In this research, we report that Glab, a major component of licorice, specifically inhibits the cGAS-STING signaling pathway by inhibiting the level of type I interferon and inflammatory cytokines (IL-6 and TNF-α). In addition, Glab has a therapeutic effect on innate immune diseases caused by abnormal cytoplasmic DNA in Trex1-deficient mice. Mechanistically, Glab can specifically inhibit the interaction of STING with IRF3.

Conclusion: Glab is a specific inhibitor of the cGAS-STING signaling pathway and may be used in the clinical therapy of cGAS-STING pathway-mediated autoimmune diseases.

Keywords
Autoimmune diseases; Glabridin; IRF3; Type I interferon; cGAS-STING.
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