Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

Many pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid, are potent immunostimulatory molecules and promote the expression of cyclooxygenase 2 (COX-2). While the production of COX-2, and ultimately prostaglandin E 2 , could be protective, persistent induction of COX-2 leads to inflamed environments that can result in septic shock and death. Bacterial derived cyclic dinucleotides (CDNs), c-di-GMP and c-di-AMP, are also PAMPs and have been shown to produce inflamed environments via the production of proinflammatory cytokines such as type I interferons. The well-characterized CDN immunostimulatory mechanism involves binding to stimulator of interferon genes (STING), which ultimately results in the phosphorylation of IRF3 or release of NF-κB to promote expression of type I IFN or pro-inflammatory cytokines. In this study, we sought to investigate if CDNs promote COX-2 expression. Using RAW macrophages as a model system, we reveal that c-di-GMP, but not c-di-AMP or the host-derived 2′,3′-cGAMP, promotes COX-2 expression. Using analogues of CDNs, we show that the presence of two guanines and two 3′,5′-phosphodiester linkages are requirements for the promotion of COX-2 expression by cyclic dinucleotides. Both c-di-GMP and LPS inductions of COX-2 expression in RAW macrophages are STING-independent and are regulated by Tpl2-MEK-ERK-CREB signaling; inhibitors of Tpl2, MEK, and ERK could attenuate COX-2 expression promoted by c-di-GMP. This work adds to the growing body of evidence that cyclic dinucleotides regulate pathways other than the STING−TBK1−IRF3 axis. Additionally, the differential COX-2 induction by c-di-GMP but not c-di-AMP or cGAMP suggests that the type and level of inflammation could be dictated by the nucleotide signature of the invading pathogen.

Cyclic dinucleoties, such as cGAMP, c-di-GMP and c-di-AMP, are fascinating second messengers with diverse roles in both prokaryotes and eukaryotes.

The cGAS-STING axis plays an important role in protecting higher organisms against invading pathogens or cancer by promoting the production of cytokines and interferons. However, persistent or uncontrolled activation of...