Microbially-Induced Exosomes from Dendritic Cells Promote Paracrine Immune Senescence: Novel Mechanism of Bone Degenerative Disease in Mice
Open accessAbstract
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 our group 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. We 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.
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Pg-induced or periodontitis-associated exosomes transmit senescence to bystander gingival immune cells.
“We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo.”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
The Results section reports that exosomes from Pg-infected dendritic cells were taken up by gingival dendritic and T cells in mice, promoted senescence, and increased alveolar bone loss. However, the Discussion explicitly says that the presence of gingipains or other bacterial antigens in those exosomes remains to be determined, so the citing sentence's cargo claim is not supported. Our copy provides no page numbers for these passages. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPg-induced exosomes contain Pg antigens including gingipains and fimbriae adhesin proteins.
“The resulting EXO contain Pg antigens including gingipains and fimbriae adhesin proteins, which locally transmit and amplify immune senescence to bystander immune cells [17,19].”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
The Discussion states that Pg-induced dendritic-cell exosomes express the Pg Mfa1 fimbrial protein, supporting the fimbriae portion of the claim. It also says the presence of gingipains or other bacterial antigens in these exosomes remains to be elucidated, so it does not support the claim that they contain gingipains. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPg-induced exosomes of the senescence-associated secretory phenotype express integrins and lectins that promote cell binding at the inflamed site.
“Pg-induced EXO of the SASP express integrins and lectins that promote cell binding at the inflamed site [19,20].”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
The Results report that Pg-induced dendritic-cell exosomes were taken up by dendritic cells and CD4+ T cells in mouse gingival tissue. The Discussion says previously studied therapeutic dendritic-cell exosomes had high affinity for inflamed gingival sites, but does not establish that affinity for Pg-induced exosomes. Neither passage says Pg-induced exosomes express integrins or lectins, or that those molecules promote binding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPg infection-induced periodontitis stimulates senescence in gingival tissues and alveolar bone.
“Our work has shown that Pg infection-induced PD stimulates senescence in gingival tissues and alveolar bone [19].”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
The Results section reports that ligature-induced periodontitis increased gingival senescence markers and that Pg gavage further increased a gingival marker in young mice. It also reports increased alveolar bone loss, but does not show that cells in the alveolar bone became senescent. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPg-induced exosomes are enriched with virulence factors from Pg including gingipains, enabling them to disrupt barrier functions of the epithelium and penetrate through interstitial spaces and lymphatics to enter systemic circulation.
“Moreover, those EXO are enriched with virulence factors from Pg including gingipains, a potent proteolytic enzyme, enabling them to disrupt barrier functions of the epithelium and penetrate through interstitial spaces and lymphatics to find their way into systemic circulation.”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
The Discussion says Pg-induced dendritic-cell exosomes express the Pg Mfa1 fimbrial protein and notes that exosomes can travel to distant sites. But it explicitly says the presence of gingipains in these exosomes remains to be determined. It does not establish epithelial-barrier disruption or the proposed route through interstitial spaces and lymphatics into systemic circulation. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Pg infection induces senescence in gingival tissues of PD mice and increases the release of pathogenic exosomes that carry pathogen-related and SASP molecules to distant bystander brain cells.
“These data suggest that Pg infection induces senescence in gingival tissues of PD mice [19] and increases the release of pathogenic EXO that carry pathogen-related and SASP molecules to distant bystander brain cells.”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
Pg-induced exosomes induce alveolar bone loss in mice in vivo.
“We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo.”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
PD exosomes could transmit senescence to gingival immune cells, including dendritic cells and T cells.
“Our group showed previously that PD EXO could transmit senescence to gingival immune cells, including DCs and Tells [17,19].”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
The purity of PD exosomes was approximately 99% and there was a lack of significant Pg outer membrane vesicles.
“The purity of PD EXO (~99%) and lack of significant Pg outer membrane vesicles (OMV) were confirmed as previously described [19].”
From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [19]
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- Authors
- Elsayed, R., Elashiry, M., Liu, Y., Morandini, A. C., El-Awady, A., Elashiry, M. M., Hamrick, M., & Cutler, C. W.
- Affiliations
- Augusta University (US)
- Ain Shams University (EG)
- Corresponding author
- Cutler, Christopher W.
- ORCID
- Venue
- Aging and disease
- Publisher
- Aging and Disease
- Published
- 2023
- Volume
- 14
- Issue
- 1
- Pages
- 136
- ISSN
- 2152-5250 (ISSN-L)
- PMC
- PMC9937696
- OpenAlex
- W4312522259
- Cited by
- 40
- References
- 53
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 9 · 2023: 5 · 2022: 1
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Aging and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Augusta University
- National Institutes of Health (1s10od025177-01)
- National Institute of Dental and Craniofacial Research (R01 DE14328, R01DE014328, R01DE029468)
- Topics
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- periodontitis, immunosenescence, dendritic cells, exosomes, senescence-associated secretory phenotype, Porphyromonas gingivalis, oral dysbiosis, alveolar bone loss, aging, senolytic therapy, rapamycin, T cells, antigen presentation, ligature-induced periodontitis, beta-galactosidase, p16INK4a, p21
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