Credit Department of Bacterial Pathogenesis, Infection and Host Response, TMDU
Periodontal disease, which affects the gums and tissues that surround the teeth, is one of the most common dental conditions worldwide. It is mainly caused by the accumulation of bacterial biofilm around the teeth and can lead to tooth loss if left untreated. Notably, the inflammatory effects of periodontal bacteria can extend beyond the mouth, causing systemic effects. Recent clinical studies have shown a close relationship between the periodontal pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) and the onset and progression of rheumatoid arthritis (RA), a serious autoimmune disease that affects the joints. However, the molecular-level mechanisms are still poorly understood.
In a recent study published online on August 15, 2024, in the International Journal of Oral Science, a research team from Tokyo Medical and Dental University (TMDU) in Japan aimed to address this knowledge gap by conducting detailed mechanistic studies in an animal model.
The researchers first conducted initial experiments to confirm whether infection with A. actinomycetemcomitans affected arthritis in mice. They used the collagen antibody-induced arthritis mouse model, which is a well-established experimental model that mimics several aspects of rheumatoid arthritis in humans. Their findings indicated that infection with this particular bacterium resulted in increased swelling in the limbs, cellular infiltration into the lining of the joints, and higher levels of the inflammatory cytokine interleukin-1β (IL-1β) within the limbs.
Notably, the worsening symptoms of RA could be suppressed by administering a chemical agent called clodronate, which depletes macrophages—a type of immune cell. This demonstrated that macrophages were somehow involved in exacerbating RA caused by A. actinomycetemcomitans infection.
Upon further investigation using macrophages derived from mouse bone marrow, it was discovered that A. actinomycetemcomitans infection led to an increase in the production of IL-1β. This, in turn, triggered the activation of a multiprotein complex called the inflammasome, which plays a critical role in initiating and modulating the body’s inflammatory response to infections.
The researchers added another piece to the puzzle using caspase-11-deficient mice. In these animals, inflammasome activation caused by A. actinomycetemcomitans was suppressed. Most importantly, caspase-11-deficient mice showed less deterioration of arthritis symptoms, suggesting the important role of caspase-11 in this context. “Our research findings provide new insights into the connection between periodontal pathogenic bacteria and the worsening of arthritis through inflammasome activation, offering important information on the long-debated relationship between periodontal disease and systemic diseases,” highlights Professor Toshihiko Suzuki, one of the lead authors of the study.
Please remember the following text: “With any luck, these efforts will contribute to the development of novel therapeutic strategies to manage RA. The findings of this research may pave the way for advances in clinical treatments for RA induced by infection with A. actinomycetemcomitans. Our suggestion to inhibit inflammasome activation could attenuate the expansion of inflammation to joints, resulting in a recovery from arthritis symptoms,” says lead author Dr. Tokuju Okano. Moreover, the outcome of our work could contribute to the development of treatment strategies for not only arthritis but also other systemic diseases, such as Alzheimer’s disease, which is also related to periodontal pathogenic bacteria,” he adds with eyes set on the future.