Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?

Aquino-Martínez, Rubén; Khosla, Sundeep; Farr, Joshua N.; Monroe, David G.

doi:10.3390/ijms21207441

Cited by 31 publications

(33 citation statements)

References 159 publications

(206 reference statements)

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“…Microbial-induced senescence has been variously attributed to DNA damage by bacterial genotoxins ( Aquino-Martinez et al., 2020 ), oxidative stress induction and ROS production ( Aquino-Martinez et al., 2020 ; Humphreys et al., 2020 ) or persistent activation of TLR4-NF-KB-P21-P53 pathway ( Feng et al., 2014 ). In the present study, the impairment of maturation of yDCs and oDCs, was accompanied by a robust IL-1b, TNFa and IL6 response, consistent with an inflammasome mediated response to P.gingivalis ( Arjunan et al., 2016 ; Tyagi et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

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

Elsayed

Elashiry

Liu

et al. 2021

Front. Cell. Infect. Microbiol.

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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 p21Waf1/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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Section: Discussionmentioning

confidence: 99%

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

Elsayed

Elashiry

Liu

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Host immunity paradoxically perpetuates periodontal disease severity via further promoting microbial dysbiosis ( Ebersole et al., 2013 ; Cekici et al., 2014 ). In line with this concept, emerging evidence suggests that chronic inflammation in the periodontium further promotes inflammatory processes and tissue destruction via cellular senescence among healthy resident cells that are chronically exposed to an inflammatory environment ( Aquino-Martinez et al., 2020 ). Although ROS can protect against invading bacteria, they can also cause harm to healthy host cells, thus inducing stress-mediated DNA damage ( Barzilai and Yamamoto, 2004 ).…”

Section: Better Safe Than Sorry? the Necessities And Pitfalls Of Periodontal Immunitymentioning

confidence: 97%

Periodontal Disease: The Good, The Bad, and The Unknown

Sedghi

Bacino

Kapila

2021

Front. Cell. Infect. Microbiol.

162

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Periodontal disease is classically characterized by progressive destruction of the soft and hard tissues of the periodontal complex, mediated by an interplay between dysbiotic microbial communities and aberrant immune responses within gingival and periodontal tissues. Putative periodontal pathogens are enriched as the resident oral microbiota becomes dysbiotic and inflammatory responses evoke tissue destruction, thus inducing an unremitting positive feedback loop of proteolysis, inflammation, and enrichment for periodontal pathogens. Keystone microbial pathogens and sustained gingival inflammation are critical to periodontal disease progression. However, recent studies have revealed the importance of previously unidentified microbes involved in disease progression, including various viruses, phages and bacterial species. Moreover, newly identified immunological and genetic mechanisms, as well as environmental host factors, including diet and lifestyle, have been discerned in recent years as further contributory factors in periodontitis. These factors have collectively expanded the established narrative of periodontal disease progression. In line with this, new ideologies related to maintaining periodontal health and treating existing disease have been explored, such as the application of oral probiotics, to limit and attenuate disease progression. The role of systemic host pathologies, such as autoimmune disorders and diabetes, in periodontal disease pathogenesis has been well noted. Recent studies have additionally identified the reciprocated importance of periodontal disease in potentiating systemic disease states at distal sites, such as in Alzheimer’s disease, inflammatory bowel diseases, and oral cancer, further highlighting the importance of the oral cavity in systemic health. Here we review long-standing knowledge of periodontal disease progression while integrating novel research concepts that have broadened our understanding of periodontal health and disease. Further, we delve into innovative hypotheses that may evolve to address significant gaps in the foundational knowledge of periodontal disease.

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“…Prolonged exposure to LPS causes accelerated senescence in different cell types, including adipocyte precursors [ 122 ], microglial cells [ 123 ], and pulmonary epithelial cells [ 124 ]. Recent evidence indicates that cells can undergo DNA damage-driven cellular senescence as result of repeated exposure to P. gingivalis LPS [ 125 , 126 ]. Although it is recognized that senescent cells contribute to deteriorating their local environment, these dysfunctional cells could also facilitate pathogen infection.…”

Section: Could Periodontal Bacteria Dissemination Into the Lower Rmentioning

confidence: 99%

Severe COVID-19 Lung Infection in Older People and Periodontitis

Aquino-Martínez

Hernández-Vigueras

2021

JCM

Self Cite

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Periodontal bacteria dissemination into the lower respiratory tract may create favorable conditions for severe COVID-19 lung infection. Once lung tissues are colonized, cells that survive persistent bacterial infection can undergo permanent damage and accelerated cellular senescence. Consequently, several morphological and functional features of senescent lung cells facilitate SARS-CoV-2 replication. The higher risk for severe SARS-CoV-2 infection, the virus that causes COVID-19, and death in older patients has generated the question whether basic aging mechanisms could be implicated in such susceptibility. Mounting evidence indicates that cellular senescence, a manifestation of aging at the cellular level, contributes to the development of age-related lung pathologies and facilitates respiratory infections. Apparently, a relationship between life-threatening COVID-19 lung infection and pre-existing periodontal disease seems improbable. However, periodontal pathogens can be inoculated during endotracheal intubation and/or aspirated into the lower respiratory tract. This review focuses on how the dissemination of periodontal bacteria into the lungs could aggravate age-related senescent cell accumulation and facilitate more efficient SARS-CoV-2 cell attachment and replication. We also consider how periodontal bacteria-induced premature senescence could influence the course of COVID-19 lung infection. Finally, we highlight the role of saliva as a reservoir for both pathogenic bacteria and SARS-CoV-2. Therefore, the identification of active severe periodontitis can be an opportune and valid clinical parameter for risk stratification of old patients with COVID-19.

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Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?

Cited by 31 publications

References 159 publications

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

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

Periodontal Disease: The Good, The Bad, and The Unknown

Severe COVID-19 Lung Infection in Older People and Periodontitis

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