The role of cGAS/STING in intestinal immunity

Wottawa, Felix; Bordoni, Dora; Baran, Nathan; Rosenstiel, Philip; Aden, Konrad

doi:10.1002/eji.202048777

Cited by 35 publications

(19 citation statements)

References 151 publications

(259 reference statements)

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“…Our work demonstrated that the cGAS-STING-type I IFN signaling axis is critical for the regulation of egg granuloma formation in the liver of schistosome-infected mice. Notably, the cGAS-STING pathway has been implicated as being critical for the regulation of the homeostasis of intestinal immunity [ 41 – 44 ]. Moreover, the intestine is an important organ for the deposition of eggs [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner

Liang

Shen

et al. 2022

PLoS Pathog

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Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition receptors are important to sense invading Schistosoma, triggering an innate immune response, and subsequently shaping adaptive immunity. Cyclic GMP-AMP synthase (cGAS) was identified as a major cytosolic DNA sensor, which catalyzes the formation of cyclic GMP-AMP (cGAMP), a critical second messenger for the activation of the adaptor protein stimulator of interferon genes (STING). The engagement of STING by cGAMP leads to the activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and the subsequent type I interferon (IFN) response. cGAS is suggested to regulate infectious diseases, autoimmune diseases, and cancer. However, the function of cGAS in helminth infection is unclear. In this study, we found that Cgas deficiency enhanced the survival of mice infected with S. japonicum markedly, without affecting the egg load in the liver. Consistently, Cgas deletion alleviated liver pathological impairment, reduced egg granuloma formation, and decreased fibrosis severity. In contrast, Sting deletion reduced the formation of egg granulomas markedly, but not liver fibrosis. Notably, Cgas or Sting deficiency reduced the production of IFNβ drastically in mice infected with S. japonicum. Intriguingly, intravenous administration of recombinant IFNβ exacerbated liver damage and promoted egg granuloma formation, without affecting liver fibrosis. Clodronate liposome-mediated depletion of macrophages indicated that macrophages are the major type of cells contributing to the induction of the type I IFN response during schistosome infection. Moreover, cGAS is important for type I IFN production and phosphorylation of TBK1 and IRF3 in response to stimulation with S. japonicum egg- or adult worm-derived DNA in macrophages. Our results clarified the immunomodulatory effect of cGAS in the regulation of liver granuloma formation during S. japonicum infection, involving sensing schistosome-derived DNA and producing type I IFN. Additionally, we showed that cGAS regulates liver fibrosis in a STING-type I–IFN-independent manner.

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Section: Discussionmentioning

confidence: 99%

cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner

Liang

Shen

et al. 2022

PLoS Pathog

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“…TMEM173, the gene that codes for STING, has been found to be hypomethylated in the GI epithelium of pediatric IBD patients, which could lead to overexpression and overactivity of STING in IECs from IBD patients ( Howell et al, 2018 ). In support of this theory, IBD patients express a wide variety of IFN-regulated genes (IRGs) with higher IFN signatures associated with therapeutic failure ( Coskun et al, 2013 ; Andreou et al, 2020 ; Wottawa et al, 2021 ). A recent paper further links cGAS and inflammsome signalling to colitis ( Ma et al, 2020 ).…”

Section: Lps-independent Activators Of Caspases-4 and -5mentioning

confidence: 97%

Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease

Smith

Creagh

2022

Front. Pharmacol.

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Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract, associated with high levels of inflammatory cytokine production. Human caspases-4 and -5, and their murine ortholog caspase-11, are essential components of the innate immune pathway, capable of sensing and responding to intracellular lipopolysaccharide (LPS), a component of Gram-negative bacteria. Following their activation by LPS, these caspases initiate potent inflammation by causing pyroptosis, a lytic form of cell death. While this pathway is essential for host defence against bacterial infection, it is also negatively associated with inflammatory pathologies. Caspases-4/-5/-11 display increased intestinal expression during IBD and have been implicated in chronic IBD inflammation. This review discusses the current literature in this area, identifying links between inflammatory caspase activity and IBD in both human and murine models. Differences in the expression and functions of caspases-4, -5 and -11 are discussed, in addition to mechanisms of their activation, function and regulation, and how these mechanisms may contribute to the pathogenesis of IBD.

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“…Recently, it has been found that excessive STING signaling can disrupt calcium homeostasis and render T cells hyperresponsive to ER stress, which may cause prolonged activation of UPR and ER stress. 47 However, the long-term activation of UPR is associated with many pathologies, including metabolic diseases (eg, type 2 diabetes), autoimmune disease (eg, UC), and cancer. Notably, UPR constitutes a highly conserved and intricately regulated group of pathways which aim to initially rebuild homeostasis by stimulating genes involved in protein folding and antioxidant mechanisms.…”

Section: Apoptosis and Er Stressmentioning

confidence: 99%

Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis

Wan

Yang

Jiang

et al. 2021

Inflammatory Bowel Diseases

106

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Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.

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The role of cGAS/STING in intestinal immunity

Cited by 35 publications

References 151 publications

cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner

cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner

Caspase-4 and -5 Biology in the Pathogenesis of Inflammatory Bowel Disease

Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis

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