cGAS-STING signaling pathway in intestinal homeostasis and diseases

Yuchen Yang; Li Wang; Ivonne Peugnet-González; Daniela Parada-Venegas; Gerard Dijkstra; Klaas Nico Faber

doi:10.3389/fimmu.2023.1239142

cGAS-STING signaling pathway in intestinal homeostasis and diseases

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

Authors

Yuchen Yang¹, Li Wang¹, Ivonne Peugnet-González², Daniela Parada-Venegas¹, Gerard Dijkstra¹, Klaas Nico Faber¹

Affiliations

¹ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
² Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

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.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

DNA
Homeostasis
Membrane Proteins* / metabolism
Nucleotidyltransferases / metabolism
Signal Transduction* / physiology

Substances

Membrane Proteins
Nucleotidyltransferases
DNA

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.