As the aging population grows, chronic age-related bone degenerative diseases become more prevalent and severe. One such disease, periodontitis (PD), rises to 70.1% prevalence in Americans 65 years and older. PD has been linked to increased risk of other age-related diseases with more serious mortality and morbidity profiles such as Alzheimer’s disease and cardiovascular disease, but the cellular and biological mechanisms remain unclear. Recent in vitro studies from a research group at the Dental College of Georgia at Augusta University, indicate that murine dendritic cells (DCs) and T cells are vulnerable to immune senescence. This occurs through a distinct process involving invasion of DCs by dysbiotic pathogen Porphyromonas gingivalis (Pg) activating the senescence associated secretory phenotype (SASP). Exosomes of the Pg-induced SASP transmit senescence to normal bystander DC and T cells, ablating antigen presentation. The biological significance of these findings in vivo and the mechanisms involved were examined in the present study using young (4-5mo) or old (22-24mo) mice subjected to ligature-induced PD, with or without dysbiotic oral pathogen and injection of Pg-induced DC exosomes. Senescence profiling of gingiva and draining lymph nodes (LN) corroborates role of advanced age and PD in elevation of senescence biomarkers beta galactosidase (SA-β-Gal), p16 INK4A p21Waf1/Clip1, IL6, TNFα, and IL1β, with attendant increase in alveolar bone loss, reversed by senolytic agent rapamycin. Immunophenotyping of gingiva and LN revealed that myeloid CD11c+ DCs and T cells are particularly vulnerable to senescence in vivo under these conditions. Moreover, Pg-induced DC exosomes were the most potent inducers of alveolar bone loss and immune senescence, and capable of overcoming senescence resistance of LN T cells in young mice. The researchers conclude that immune senescence, compounded by advanced age, and accelerated by oral dysbiosis and its induced SASP exosomes, plays a pivotal role in the pathophysiology of experimental periodontitis.
Exosomes derived from DC infected with Pg are internalized into DCs and CD4 T cells in situ and promote alveolar bone loss
(A) Nano tracking analysis (NTA) to determine Exo number and size distribution in nanometer (nm). (B) SEM showing characteristic Exo morphology (orange arrows) (C) Immuno-gold TEM showing EXO marker, tetraspanin CD63 (D-E) Confocal microscopy images showing the uptake of Dil-labeled PgDCexo (red) in (D) CD11c+ DCs (green) and in (E) CD4+ T cells (green) in gingival tissues of mice. Nuclei were counterstained with DAPI (blue). (F) MicroCT analysis showing bone loss in young mice induced by gingival injection of PgDCexo but not iDCexo (N=6 per group).