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Cited by 64Oral microbiology and periodontitis researchTelomeres, Telomerase, and SenescenceImmune Response and Inflammation

Porphyromonas gingivalis Provokes Exosome Secretion and Paracrine Immune Senescence in Bystander Dendritic Cells

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Elsayed, Ranya, Elashiry, Mahmoud, Liu, Yutao, El-Awady, Ahmed, Hamrick, Mark, Cutler, Christopher W.·2021·Frontiers in Cellular and Infection Microbiology
DOI 10.3389/fcimb.2021.669989PMC PMC8204290
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Abstract

Periodontitis is a disease of ageing or inflammaging, and is comorbid with other more severe age-related chronic diseases. With advanced age comes an increase in accumulation of senescent cells that release soluble and insoluble pro-inflammatory factors collectively termed the senescence associated secretory phenotype (SASP). In the present report, we examined whether immune cells typical of those at the oral mucosa-microbe interface, are vulnerable to cellular senescence (CS) and the role of dysbiotic oral pathogen Porphyromonas gingivalis. Bone marrow-derived dendritic cells (DCs) from young (yDCs) and old (oDCs) mice were co-cultured in vitro with CS inducer doxorubicin or P.gingivalis (Pg), plus or minus senolytic agent rapamycin. CS profiling revealed elevated CS mediators SA-β-Gal, p16 INK4A, p53, and p21 Waf1/Clip1 in oDCs, or yDCs in response to doxorubicin or P. gingivalis, reversible with rapamycin. Functional studies indicate impaired maturation function of oDCs, and yDC exposed to P. gingivalis; moreover, OVA-driven proliferation of CD4+ T cells from young OTII transgenic mice was impaired by oDCs or yDCs+Pg. The SASP of DCs, consisting of secreted exosomes and inflammasome-related cytokines was further analyzed. Exosomes of DCs cocultured with P. gingivalis (PgDCexo) were purified, quantitated and characterized. Though typical in terms of size, shape and phenotype, PgDCexo were 2-fold greater in number than control DCs, with several important distinctions. Namely, PgDCexo were enriched in age-related miRNAs, and miRNAs reported to disrupt immune homeostasis through negative regulation of apoptosis and autophagy functions. We further show that PgDCexo were enriched in P. gingivalis fimbrial adhesin protein mfa1 and in inflammasome related cytokines IL-1β, TNFα and IL-6. Functionally PgDCexo were readily endocytosed by recipient yDCs, amplifying functional impairment in maturation and ability to promote Ova-driven proliferation of OTII CD4+ T cells from young mice. In conclusion P. gingivalis induces premature (autocrine) senescence in DCs by direct cellular invasion and greatly amplifies senescence, in paracrine, of bystander DCs by secretion of inflammatory exosomes. The implications of this pathological pathway for periodontal disease in vivo is under investigation in mouse models.

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  • Cellular senescence increases biogenesis and secretion of exosomes as part of the senescence-associated secretory phenotype.

    “Cellular secretion of small extracellular vesicles or exosomes (EXO) increases with aging as part of the senescence-associated secretory phenotype (SASP).”

    From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [17]

    The Introduction identifies exosomes as part of the senescence-associated secretory phenotype. The Discussion reports increased exosome production by dendritic cells infected with P. gingivalis, but does not establish that exosome secretion increases with aging generally. The paper therefore supports the SASP component, not the claimed age-related increase. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • 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 [17]

    The Introduction and Discussion report that exosomes from P. gingivalis-infected dendritic cells transmit senescence to recipient young dendritic cells in vitro. The study used bone marrow-derived cells, not bystander gingival cells, and identifies the Pg antigen Mfa1 but does not establish that the exosomes contain gingipains. The Discussion says in vivo studies were underway, so the cited paper does not support the sentence’s claim that these exosomes induced alveolar bone loss in mice. Page numbers were not provided in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Pg-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 [17]

    The Results section reports that exosomes from P. gingivalis-infected dendritic cells contain the Mfa1 fimbrial adhesin, and the Discussion reports that these exosomes promote senescence in bystander dendritic cells. The paper does not report gingipains in those exosomes; a search for “gingipain” found no supporting passage. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 [17]

    The Discussion (page not provided) reports that exosomes from P. gingivalis-exposed dendritic cells induced senescence in bystander dendritic cells. The Abstract (page not provided) reports impaired CD4+ T-cell proliferation, not transmission of senescence to T cells. The experiments used mouse bone marrow-derived dendritic cells in vitro, so the paper does not establish the claim for gingival immune cells. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Elsayed, R., Elashiry, M., Liu, Y., El-Awady, A., Hamrick, M., & Cutler, C. W.
Affiliations
Augusta University (US)
Corresponding author
Cutler, Christopher W.
ORCID
Venue
Frontiers in Cellular and Infection Microbiology
Publisher
Frontiers Media SA
Published
2021-06-01
Volume
11
Pages
669989-669989
ISSN
2235-2988 (ISSN-L)
DOI
10.3389/fcimb.2021.669989
PMC
PMC8204290
OpenAlex
W3169149128
Cited by
64
References
11
Citations by year
2026: 11 · 2025: 18 · 2024: 16 · 2023: 7 · 2022: 9 · 2021: 3
FWCI
9.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Augusta University
  • Carlos and Marguerite Mason Trust
  • National Institute of Dental and Craniofacial Research (R01DE029468)
Topics
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
Porphyromonas gingivalis, periodontitis, immunosenescence, dendritic cells, senescence-associated secretory phenotype, exosomes, paracrine senescence, doxorubicin-induced senescence, rapamycin, dendritic cell maturation, CD4+ T cell proliferation, inflammaging, oral microbiota dysbiosis, senolytics, IL-1β
MeSH terms
Animals, Dendritic Cells, Periodontitis, Fimbriae, Bacterial, Porphyromonas gingivalis, Mice, Exosomes

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