Bacterial Cyclic Dinucleotides and the cGAS-cGAMP-STING Pathway: A Role in Periodontitis?

Abstract

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.

Keywords: STING; bacterial recognition; cyclic dinucleotides; nucleic acid; periodontitis.

Figure 1

(A) Clinical appearance of advanced periodontitis in a 32-year-old, otherwise healthy, female patient. Heavy dental biofilm deposits and signs of gingival inflammation are clinically visible. (B) Panoramic radiograph of the patient reveals generalized alveolar bone destruction and its severity (by courtesy of Mustafa Yilmaz, Biruni University, Istanbul, Turkey).

Figure 2

Localizations of STING, TBK1, and IRF3 in gingival tissues with good periodontal health (upper row) and with periodontitis (lower row). White arrows indicate examples of zones with prominent staining. Periodontally healthy gingival tissue was excised during a crown lengthening procedure from a 30-year-old female. The gingival tissue sample with periodontitis was excised during a flap surgery. Both surgical interventions were part of the respective patients’ routine periodontal treatment, and the samples belong to the sample collection of Dr. Gökhan Kasnak, Cerrahpasa University, Istanbul, with the ethical permission no: Istanbul University 2017/41. Histological techniques were performed according to the previously described method [39], using primary antibodies of STING (PA5-26808, Thermo Fisher, Rockford, IL, USA), IRF3 (PA5-87506, Thermo Fisher), and TBK1 (PA5-17478, Thermo Fisher).

Figure 3

Diagram illustrating the cellular response of three types of periodontal resident cells (keratinocytes, fibroblasts, and macrophages) to bacterial cyclic dinucleotides.

Figure 4

Selected STING inhibitors.

Figure 5

Chemical structures of STING agonists.