cGAS-STING signaling pathway in intestinal homeostasis and diseases

Abstract

The intestinal mucosa is constantly exposed to commensal microbes, opportunistic pathogens, toxins, luminal components and other environmental stimuli. The intestinal mucosa consists of multiple differentiated cellular and extracellular components that form a critical barrier, but is also equipped for efficient absorption of nutrients. Combination of genetic susceptibility and environmental factors are known as critical components involved in the pathogenesis of intestinal diseases. The innate immune system plays a critical role in the recognition and elimination of potential threats by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This host defense is facilitated by pattern recognition receptors (PRRs), in which the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has gained attention due to its role in sensing host and foreign double-stranded DNA (dsDNA) as well as cyclic dinucleotides (CDNs) produced by bacteria. Upon binding with dsDNA, cGAS converts ATP and GTP to cyclic GMP-AMP (cGAMP), which binds to STING and activates TANK binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), inducing type I interferon (IFN) and nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokines, which have diverse effects on innate and adaptive immune cells and intestinal epithelial cells (IECs). However, opposite perspectives exist regarding the role of the cGAS-STING pathway in different intestinal diseases. Activation of cGAS-STING signaling is associated with worse clinical outcomes in inflammation-associated diseases, while it also plays a critical role in protection against tumorigenesis and certain infections. Therefore, understanding the context-dependent mechanisms of the cGAS-STING pathway in the physiopathology of the intestinal mucosa is crucial for developing therapeutic strategies targeting the cGAS-STING pathway. This review aims to provide insight into recent findings of the protective and detrimental roles of the cGAS-STING pathway in intestinal diseases.

A molecular subtyping associated with the cGAS-STING pathway provides novel perspectives on the treatment of ulcerative colitis

“…On the one hand, activation of cGAS-STING signaling is associated with the severity of intestinal inflammation. On the other hand, it plays a key role in preventing tumorigenesis and infection 13 . Colorectal cancer (CRC) patients with high STING expression had increased intratumoral CD8 + T cells infiltration and decreased frequency of lymphovascular infiltration.…”

“…The latest study shows that the clinical development of inhibitor has begun, and clinical trials are planned to begin 12 . Interestingly, previous study has reported that the cGAS-STING pathway is involved in the pathogenesis, progression, and therapeutic response of UC 13 . The level of STING is increased in the colon of patients with UC 14 .…”

Focus on the cGAS-STING Signaling Pathway in Sepsis and Its Inflammatory Regulatory Effects

“… 44 The activation of IRF3(interferon regulatory factor 3) and its subsequent induction of IFN-I and other Interferon-stimulated genes (ISGs) constitute the most comprehensively understood process governed by the cGAS-STING pathway’s activation. 45 Furthermore, IRF3 activity is also crucial for the induction of numerous other target genes, including those encoding inflammatory cytokines 46 . In the septic state, cGAS becomes activated when the host cell recognizes the pathogen’s DNA, thereby activating STING, which then promotes IFN-I expression through the IRF3 pathway.…”

“… 53 , 82 Furthermore, the STING pathway activation is implicated in regulating the intestinal immune response to bacterial infections and inflammation in the context of sepsis-related intestinal mechanical barrier damage. 46 Additionally, some studies suggest that STING pathway activation might influence septic enteric mechanical barrier injury by modulating the stability of the intestinal flora. 83 Erttmann SF et al discovered that the intestinal flora activates the cGAS-STING signaling pathway in the organism’s cytoplasm, maintaining basal systemic IFN-I production levels, as shown through a series of innate immune pathway-deficient mouse models and in vitro cell culture experiments, combined with 16S rDNA and high-throughput transcriptome sequencing.…”

The role of cGAS in epithelial dysregulation in inflammatory bowel disease and gastrointestinal malignancies

“…A growing body of research demonstrates the importance of abnormal cGAS signaling in the pathogenesis of various GI diseases. In ulcerative colitis, abnormal activation of cGAS contributes to the dysregulation of intestinal epithelial autophagy, epithelial cell integrity, and innate immune responses ( Ke et al, 2022 ; Yang et al, 2023 ). Meanwhile, in GI cancers, cGAS-mediated pathways have been shown to be both oncogenic and tumor suppressive ( Ke et al, 2022 ; Yang et al, 2023 ).…”