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Review
. 2023 Sep 14:14:1239142.
doi: 10.3389/fimmu.2023.1239142. eCollection 2023.

cGAS-STING signaling pathway in intestinal homeostasis and diseases

Yuchen Yang  1 , Li Wang  1 , Ivonne Peugnet-González  2 , Daniela Parada-Venegas  1 , Gerard Dijkstra  1 , Klaas Nico Faber  1
Affiliations
Review

cGAS-STING signaling pathway in intestinal homeostasis and diseases

Yuchen Yang et al. Front Immunol. .

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.

Keywords: STING; cGAS; colorectal cancer; inflammatory bowel diseases; intestinal infections; intestinal ischemia/reperfusion.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the cGAS-STING pathway. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is involved in multiple biological processes. Cytoplasmic cGAS can recognize exogenous and endogenous double-strand DNA (dsDNA) from various sources, including DNA viruses, reverse-transcription of RNA viruses, bacteria, parasites, cell debris, extracellular vesicles (EVs), as well as the damaged mitochondria- and self-DNA from the nucleus. Interferon-gamma inducible protein 16 (IFI16) directly interacts with cytosolic dsDNA, cGAS and STING, facilitating the activation of cGAS and STING. Activated cGAS then catalyzes the synthesis of the second messenger cyclic GMP-AMP (cGAMP) from ATP and GTP. Cyclic dinucleotides (CDNs) of bacteria, cGAMP or dsDNA binds to endoplasmic reticulum (ER)-located STING that is retained by stromal interaction molecule 1 (STIM1) and initiates STING translocation to the Golgi apparatus via coat protein complex II (COPII) and ER-Golgi intermediate compartment (ERGIC). Then STING recruits and phosphorylates TBK1 and IRF3 and simultaneously activates IΚB kinase (IKK) and signal transducer and activator of transcription 6 (STAT6), triggering the transcription of pro-inflammatory cytokines, antiviral chemokines, IFN-stimulated genes and Type I IFN. In parallel, some cGAMP can be delivered to the outside of cells through the GAP junction, binding with the plasmatic membrane (pmSTING) and driving the same activation response or enter other cells through solute carrier family 19 member 1 (SLC19A1) and SLC46A2. The rest of cGAMP can be degraded by membrane hydrolase ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). Post-Golgi STING vesicles are either fused or encapsulated by lysosomes and gradually eliminated. After type I IFN and cytokines (e.g. IL-6) are secreted outside, they can bind to IFN receptor and cytokine receptor (e.g. IL-6R/GP130) on the membrane respectively and then activate Janus kinases (JAK)-STAT signaling pathway. Created with BioRender.com.
Figure 2
Figure 2
Overview of the STING deficiency (Sting -/-) and STING gain-of-function (Sting +/N153s) on mice models. Created with BioRender.com.
Figure 3
Figure 3
Role of cGAS-STING signaling activation in health and intestinal diseases. In the context of health (A), the intricate symbiotic interplay between the intestinal microbiota and the colonic mucosa relies on the intrinsic STING pathway present in both epithelial and immune cells. This dynamic interaction facilitates the defense against pathogenic infections by stimulating the secretion of type I interferons (IFN-I) and Interferon-stimulated gene (ISGs), reinforcing the integrity and regeneration of the epithelial barrier, promoting the production of antimicrobial peptides by Paneth cells, mucus synthesis by goblet cells, secretory IgA (SIgA) expression by plasma cells. This mutually beneficial relationship is crucial for maintaining immune cell homeostasis and establishing a harmonious and balanced gut environment. Colorectal cancer (B) is marked by an imbalanced state of the microbiota. Within this context, the release of DNA from dead tumor cells triggers the activation of the STING pathway in tumor cells and immune cells. This dual activation cascade promotes a pro-inflammatory immune response within the tumor microenvironment, effectively impeding tumorigenesis. Notably, STING activation facilitates the infiltration, activation, proliferation, and cross-priming of dendritic cells, macrophages, CD8+ T cells, and NK cells. Inflammatory bowel disease (IBD) (C) also manifests dysbiosis and the translocation of pathogenic microorganisms into the lamina propria (LP) due to a compromised epithelial barrier. Bacterial DNA or cyclic dinucleotides (CDNs) and self-DNA derived from damaged cells, including double-stranded DNA (dsDNA) and mitochondrial DNA (mtDNA), induce the activation of STING in both epithelial and immune cells, thereby exacerbating intestinal mucosal inflammation. Furthermore, STING activation and its downstream effectors elicit endoplasmic reticulum (ER) stress, and apoptosis, contributing to epithelial barrier damage. Consequently, macrophage infiltration and activation, along with T cell accumulation in the LP, are promoted by STING activation, perpetuating the imbalance of pro-inflammatory cells and cytokines in IBD. Similar to IBD, intestinal injury (D) is characterized by dysbiosis, epithelial damage, and the translocation of bacteria. Bacterial DNA or CDNs and self-DNA from damaged or dead cells play a significant role in activating the STING pathway, leading to cellular death, inflammation, and intestinal barrier disruption. Furthermore, activation of the STING pathway in immune cells elevates reactive oxygen species (ROS) levels, subsequently causing lipid peroxidation and triggering the production of IFN-I and pro-inflammatory cytokines. This collective response perpetuates a state of sustained inflammation within the intestinal environment. The solid line represents effects, the dotted line represents translocation. Created with BioRender.com.
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Grants and funding

This work was supported by the China Scholarship Council (No. 202006350025 and No. 202108310110) to YY and LW. IP-G was supported by CONAHCYT (Consejo Nacional de Humanidades, Ciencias y Tecnologías, CVU: 710722. Scholarship Number: 297024). YY, LW, IP-G and DP-V were all supported by UMCG and RUG.