STING (stimulator of interferon genes), a cytoplasmic sensor for cyclic dinucleotides (CDNs), plays a crucial role as an adaptor molecule for a number of intracellular DNA receptors. The upstream DNA sensors that signal through STING include cyclic GMP-AMP synthase (cGAS), IFN-inducible proteins, and DExD/H-box helicase family proteins, highlighting an important function for STING in controlling multiple DNA recognition pathways. STING has been crucial in host defense against viral, bacterial, and eukaryotic pathogens, and also to the development of autoimmune disease. Abnormalities in this defense mechanism can underpin a spectrum of conditions, including cancer and autoinflammatory diseases. STING is thus a highly promising drug target. Recent studies have underscored the role of STING in regulating intestinal inflammation and tumorigenesis. As high levels of microbiota-derived DNA and CDNs are present in the gut, these stimuli could contribute to local activation of STING at steady state. Sting-/- mice have been reported to develop more severe colitis upon acute inflammatory insult. Our preliminary data demonstrated that T cells expressed STING at levels higher than that in dendritic cells (DCs). Furthermore, activation of STING signaling promoted T cell production of IL-10 and IL- 22 but inhibited IL-17 production, indicating that STING may potentially regulate intestinal homeostasis and colitis development by promoting anti-inflammatory IL-10/IL-22 and inhibiting proinflammatory cytokine production by T cells. In this application, we will test whether STING promotes T cell production of IL-10 and IL-22 by inducing IRF4 and AHR expression mediated by the production of type I IFNs by both T cells and dendritic cells, which would lead to the preservation of intestinal immune homeostasis and inhibition of IBD. Furthermore, we will test whether STING agonists can prevent and treat colitis.
Gut microbiota are important in the regulation of intestinal homeostasis and the pathogenesis of inflammatory bowel disease, a chronic intestinal inflammation. However, it is unclear how this occurs. We will investigate whether a cellular protein, STING, which senses gut bacterial products, promotes T cell production of IL-10, an anti-inflammatory molecule, leading to the preservation of intestinal immune homeostasis and the inhibition of inflammatory bowel disease.
