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

Frontiers in Cellular and Infection Microbiology

Mark Hamrick¹  Yutao Liu¹  Ahmed El-Awady²  Mahmoud Elashiry²  Christopher W. Cutler²  Ranya Elsayed² 

[1] Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, United States;Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, GA, United States;

关键词: (MeSH): dendritic cells;    exosomes;    immune senescence;    periodontitis;    Porphyromonas gingivalis;   

DOI  :  10.3389/fcimb.2021.669989

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

CC BY