The effect of the cyclic GMP-AMP synthase-stimulator of interferon genes signaling pathway on organ inflammatory injury and fibrosis

The cyclic GMP-AMP synthase-stimulator of interferon genes signal transduction pathway is critical in innate immunity, infection, and inflammation. In response to pathogenic microbial infections and other conditions, cyclic GMP-AMP synthase (cGAS) recognizes abnormal DNA and initiates a downstream type I interferon response. This paper reviews the pathogenic mechanisms of stimulator of interferon genes (STING) in different organs, including changes in fibrosis-related biomarkers, intending to systematically investigate the effect of the cyclic GMP-AMP synthase-stimulator of interferon genes signal transduction in inflammation and fibrosis processes. The effects of stimulator of interferon genes in related auto-inflammatory and neurodegenerative diseases are described in this article, in addition to the application of stimulator of interferon genes-related drugs in treating fibrosis.

ADU S-100 (MIW815 or ML RR-S2 CDA) Chelvanambi et al. 2021 (Chelvanambi et al., 2021) CD11c DC Mouse melanoma model ADUS-100 retards the growth of melanoma. In addition, it helps to induce the development of VN and TLS, thus enhancing the efficacy of tumor treatment. The above results were similarly seen in ADUS-100treated CD11c DC.  (Sali et al., 2015), this study demonstrated that G10 can directly agonize human-derived STING, which was also confirmed in CT26 cells. However, G10 did not have the ability to activate IRF3 and NF-κB signaling in THP-1 cells.

MC38 murine tumor models
The effect of interferon production induced by SHR1032 was stable and stronger than that of ADUS-100. It is sensitive to human STING and can activate the downstream reaction of STING in THP-1 cells and human PBMCs. In addition, SHR1032 showed an obvious tumor inhibitory effect in mice.

CF501
Liu et al. 2022  Spleen and lungs/THP-1 cells Human ACE2transgenic mice, rabbits, and rhesus macaques As a vaccine adjuvant, CF501 is more effective than cGAMP at boosting humoral and T-cell immunological activation. CF501 also effectively agonizes STING, as evidenced by a marked increase in inflammatory cytokines and chemokines in THP-1 cells. Additionally, it developed longlasting viral immunity in mice and NHPs, even for several months, to fend against SARS-CoV-2 reinfection.

ANTAGONISTS C-178/C-176
Haag et al. 2018 (Haag et al., 2018) Heart Mice deficient in Trex1 C-178 and C-176 act by inhibiting palmitoylation of STING. The degree of cardiac inflammation in mouse models of autoimmune disease was significantly reduced after treatment with the above drugs. However, these  (Shen et al., 2022) Liver/hepatocyte Mice with liver fibrosis c-176 inhibits perinuclear translocation of STING and NF-κB translocation to the nucleus. This action lowers the expression of fibronectin, which has been elevated, as well as upregulated pro-inflammatory cytokines.
Chung et al. 2019 (Chung et al., 2019) Kidney Mice deficient in TFAM C-176 attenuated TFAM deficiencyinduced kidney inflammation and fibrosis in mice, thereby improving renal function. This was manifested as a reduction in apoptosis, kidney injury, inflammation levels as well as fibrosis.

H-151
Rech et al. 2022 (Rech et al., 2022) Heart Mouse MI model H-151 reduces STING-induced interferon production and levels of cardiac inflammation. In addition, it inhibits cardiac remodeling in reperfused MI, thereby reducing myocardial hypertrophy. H-151 also contributes to the reduction of infarct size and fibrosis marker production in the heart. All of the above effects are manifested as protection of cardiac function.  (Hansen et al., 2018) Fibroblasts from SAVI patients Mice infected with HSV-2 NO2-FAs exert an inhibitory effect on palmitoylation of STING, thereby reducing the production of type I interferon.

Mice deficient in Trex1
SN-011 has a good potency and safety profile, and it competes with CDN to bind STING, thereby inhibiting STING-induced inflammatory responses. Therefore, SN-011 has significant benefits in improving autoimmune diseases and may be an effective drug for the treatment of SAVI.

ISD017
Prabakaran et al. 2021 (Prabakaran et al., 2021) Spleen and kidney/THP-1 cells and human PBMCs Mouse lupus model ISD017 acts by inhibiting the translocation of STING to the Golgi apparatus. The downstream activity of STING was inhibited by ISD017 in both mouse lupus models and samples from lupus patients, thereby reducing the extent of lupus lesions.

THP-1 cells and MEFs
Mice deficient in Trex1 Compound C reduced cGAMP in a cGAS-independent manner, thereby attenuating STING-mediated IFN production and, consequently, ISG levels. This has an ameliorative effect X6 inhibits the activity of cGAS, thereby reducing the synthesis of cGAMP. The levels of ISGs were decreased by X6 administration both in mice lacking Trex1 and in the PBMCs of SLE patients. In addition, myocardial inflammation and endocardial fibrosis in the aforementioned mice were also improved by X6.
Ru.521 (acts on cGAS) Xu et al. 2020 (Xu et al., 2020) Heart Mice with sepsis RU.521 inhibited the activation of cGAS, thereby reducing the inflammatory damage in the hearts of septic mice. In addition, inhibition of cGAS protected mice from cardiac damage caused by oxidative stress and apoptosis, thereby improving cardiac function.

Mice deficient in Trex1
Aspirin can acetylate cGAS to inhibit its activity, thereby blocking the downstream response and leading to a reduction in the production of IFNs and ISGs. In addition, the same results were also seen in PBMCs of AGS patients and in AGS mouse models.