The role of gram-positive bacteria in pulp inflammation – NF-κB as a potential therapeutic target?

• Applicant: Privatdozent Dr. Matthias Widbiller
• Subject Area: Dentistry, Oral Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518153199

Dental caries has a significant prevalence worldwide. It destroys teeth by bacteria that convert carbohydrates into organic acids. Gram-positive ones play a key role, with Streptococcus mutans in particular being distinguished by its ability to synthesize large amounts of extracellular matrix, which favors biofilm formation, and its ability to metabolize a variety of carbohydrates even at low pH. In a caries lesion, the microorganisms and their products diffuse to the pulp cavity through dentinal tubules, leading to inflammation of the dental pulp. Lipoteichoic acid (LTA), which is anchored in the cell membrane of gram-positive bacteria like S. mutans, plays a central role in deep cavities. By binding to TLR-2 on cell membranes, it triggers immune responses in the odontoblasts at the pulp-dentin-interface as well as pulp fibroblasts in the center. Intracellularly, the NF-κB signaling cascade is activated, leading to the secretion of various chemokines and cytokines to modulate the inflammation and restore tissue homeostasis. Furthermore, the dental pulp reacts by forming tertiary dentin to shield itself from the microbial irritants. Until now, the goal of caries treatment in asymptomatic teeth or those with reversible pulpitis has been to remove most of the infected dentin and to restore the tooth. When clinical symptoms demonstrate irreversible pulpitis, vital pulp therapy is no longer indicated and root canal treatment must be initiated. In the future, however, immunomodulatory therapeutics may provide an alternative to pulp removal for irreversible pulpitis by controlling pulp inflammation and allowing regeneration. Therefore, the aim of the proposed project is to investigate, whether clinically established pharmacological agents acting specifically on the NF-κB signaling pathway would be suitable for the treatment of inflammatory conditions of the dental pulp. To address the overarching question, five subprojects with specific objectives will be established. The first focuses on a novel coculture model with S. mutans and investigates whether LTA induces intranuclear translocation of NF-κB via TLR-2 activation in cells of the pulp-dentin-interface and in pulp fibroblasts, respectively. In the following, the defense responses of both cell types are studied on the one hand on cell differentiation by genetic profiling, and on the other hand on the immunological properties, especially the activation of inflammasomes and proinflammatory cytokines. In addition, antimicrobial molecules released by the cells could trigger an adaptive response in S. mutans, which will be analyzed by RNA sequencing. Finally, the potential of three clinically established drugs, acetylsalicylic acid, hydrocortisone, and tacrolimus, will be investigated to specifically control the inflammatory response in cells of the pulp-dentin interface and in dental pulp fibroblasts.

• DFG Programme: Research Grants