Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion

Abstract

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-alpha, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis.

A Systematic Literature Review on Inflammatory Markers in the Saliva of Patients with Multiple Sclerosis: A Cause or a Consequence of Periodontal Diseases

“…There is an emerging consensus that circulating pro-inflammatory molecules could act as connectors between the status of periodontal disease (PD) and the progression of neuroinflammatory or neurodegenerative diseases. This linkage is particularly apparent in individuals displaying high antibody levels against Porphyromonas gingivalis , a prevalent pathogen in PD, or those exhibiting gene expression profiles distinctly linked to this dental condition [ 11 , 18 , 19 ]. Similarly, PD shares common etiological factors with other chronic inflammatory conditions like cardiovascular diseases, diabetes mellitus, and rheumatoid arthritis, all of which are associated with systemic inflammation and abnormal immune responses similar to those observed in multiple sclerosis (MS) [ 10 , 20 ].…”