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

ABSTRACT: 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.

SUBMITTER: Liu Y

PROVIDER: S-EPMC9762484 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Liu Yuliang Y Li Yihui Y Xue Li L Xiao Jie J Li Pengyong P Xue Wanlin W Li Chen C Guo Haipeng H Chen Yuguo Y

Frontiers in pharmacology 20221205

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 sy ...[more]

PMID: 36545321

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Project description:The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway play a significant role in the production of inflammatory cytokines and type I interferons. This study aims to develop a cGAS-STING pathway-related genes (CSRs) prediction model to predict prognosis in gastric cancer (GC). In the present study, we used The Cancer Genome Atlas (TCGA), Gene Expression Omnibus databases (GEO), CIBERSORT and Tumor Immune Estimation Resource databases (TIMER). The risk model based on five hub genes (IFNB1, IFNA4, IL6, NFKB2, and TRIM25) was constructed to predict the overall survival (OS) of GC. Further univariate Cox regression (URC) and multivariate Cox regression (MCR) analyses revealed that this risk scoring model was an independent factor. The results were verified by GEO external validation set. Multiple immune pathways were assessed by Gene Set Enrichment Analysis (GSEA). TIMER analysis demonstrated that risk score strongly correlated with Macrophage, B cells and CD8 + T cells infiltration. In addition, through 'CIBERSORT' package, the higher levels of infiltration of T cell follicular assistance (P = 0.011), NK cells-activated (P = 0.034), and Dendritic cells resting (P = 0.033) exhibited in high-risk group. Kaplan-Meier (K-M) survival analysis illustrated T cells CD4 memory resting and T cells follicular helper infiltration correlated with overall survival (OS) of GC patients in TCGA and GEO databases. Altogether, the risk score model can be conveniently used to predict prognosis. The immunocyte infiltration analysis provided a novel horizon for monitoring the status of the GC immune microenvironment.Abbreviations:TCGA: The Cancer Genome Atlas databases; GEO: Gene Expression Omnibus databases; GC: Gastric cancer; CSRs: cGAS-STING pathway-related genes; DECSRs: Differential expressed cGAS-STING pathway-related genes; PCSRs: Prognosis related cGAS-STING pathway genes; URC: Univariate Cox regression analyses; MCR: Multivariate Cox regression analyses GSEA: Gene set enrichment analysis; TIIC: Tumor-infiltrating immune cell.

Project description:The innate immune DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) gene (STING) pathway exerts strong antiviral activity through downstream IFN production; however, it has been recently recognized that an IFN-independent activity of STING also plays an important role in antiviral functions. Nevertheless, the IFN-independent antiviral activity of STING is not fully understood. Here, we showed that porcine STING (pSTING) played a critical role against herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infections, and IFN-defective mutants, including pSTING pLxIS sub, S365A, and △CTT, all exhibited similar antiviral functions, compared to wild-type (WT) pSTING. Furthermore, all of these IFN-defective pSTING mutants possessed comparable autophagy activity, relative to WT pSTING, as expected. From pSTING WT, S365A, and △CTT, the residues responsible for autophagy, including L333A/R334A, Y167A/L170A, and Y245A/L248A, were mutated. Surprisingly, all of these autophagy-defective pSTING mutants still resisted the two viral infections, demonstrating that the pSTING antiviral function is independent of IFN as well as autophagy. On the other hand, all of the autophagy-defective pSTING mutants triggered cell apoptosis, which was associated with and participated in the antiviral functions. Additionally, pSTING lost its antiviral activity in TANK-binding kinase 1 (TBK1)-/- and IFN regulatory factor 3 (IRF3)-/- porcine macrophages, indicating the involvement of TBK1 and IRF3 in other STING activities such as apoptosis. Collectively, our results revealed that STING exerts both IFN- and autophagy-independent antiviral activity, and they also suggested that STING-triggered cell apoptosis resists viral infections. IMPORTANCE The IFN-independent antiviral function of the cGAS-STING pathway has attracted great attention in recent years; however, the nature of this IFN-independent antiviral function is unknown, although STING-induced autophagy has been shown to mediate the STING antiviral activity. First, we analyzed the antiviral activity through the porcine cGAS-pSTING pathway and established that pSTING signaling exerts an IFN-independent antiviral function. Second, we found that pSTING-induced IFN-independent autophagy and the antiviral activity of pSTING are independent of both IFN and autophagy. Finally, pSTING signaling activates cell apoptosis independently of IFN and autophagy, and the apoptosis is associated with antiviral activity. Our results suggest that pSTING-activated apoptosis at least partially mediates the antiviral activity or multiple pSTING-activated signals, including IFN production, nuclear factor κ light chain enhancer of activated B cells (NF-κB) expression, autophagy, and apoptosis, exert a redundant antiviral role. Thus, the work reveals a new layer of complexity in STING antiviral activity.

Dataset Information

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

Publications

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

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