TY - JOUR
T1 - Microbially-Induced Exosomes from Dendritic Cells Promote Paracrine Immune Senescence
T2 - Novel Mechanism of Bone Degenerative Disease in Mice
AU - Elsayed, Ranya
AU - Elashiry, Mahmoud
AU - Liu, Yutao
AU - Morandini, Ana C.
AU - El-Awady, Ahmed
AU - Elashiry, Mohamed M.
AU - Hamrick, Mark
AU - Cutler, Christopher W.
N1 - Publisher Copyright:
Copyright: © 2022 Elsayed R. et al.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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-βGal), p16INK4A 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.
AB - 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-βGal), p16INK4A 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.
KW - SASP
KW - dendritic cells
KW - exosomes
KW - immune senescence
KW - periodontitis
KW - porphyromonas gingivalis
UR - http://www.scopus.com/inward/record.url?scp=85140363203&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85140363203&partnerID=8YFLogxK
U2 - 10.14336/AD.2022.0623
DO - 10.14336/AD.2022.0623
M3 - Article
AN - SCOPUS:85140363203
SN - 2152-5250
VL - 14
SP - 136
EP - 151
JO - Aging and Disease
JF - Aging and Disease
IS - 1
ER -