TY - JOUR
T1 - Senescence-associated hyper-activation to inflammatory stimuli in vitro
AU - Budamagunta, Vivekananda
AU - Manohar-Sindhu, Sahana
AU - Yang, Yang
AU - He, Yonghan
AU - Traktuev, Dmitry O.
AU - Foster, Thomas C.
AU - Zhou, Daohong
N1 - Publisher Copyright:
© 2021 Budamagunta et al. All Rights Reserved.
PY - 2021
Y1 - 2021
N2 - Aging is associated with an increased susceptibility to adverse inflammatory conditions such as sepsis and cytokine storm. We hypothesized that senescent cells (SnCs) play a central role in this age-associated pathology in part due to their expression of the senescence-associated secretory phenotype (SASP), which may prime SnCs to inflammatory stimulation. To test this hypothesis, we examined the expression of various inflammatory cytokines and chemokines at the levels of gene transcription and protein production in various SnCs in vitro in response to lipopolysaccharide (LPS), interleukin-1β (IL1β), and tumor necrosis factor α (TNFα) stimulation. We found that SnCs not only expressed higher basal levels of various inflammatory cytokines and chemokines as a manifestation of the SASP, but more importantly exhibited hyper-activation of the induction of a variety of inflammatory mediators in response to LPS, IL1β and TNFα stimulation as compared with non-SnCs. This senescence-associated hyper-activation is likely mediated in part via the p38MAPK (p38) and NFkB pathways because LPS stimulation elicited significantly higher levels of p38 phosphorylation and NFkB p65 nuclear translation in SnCs when compared to their non-senescent counterparts and inhibition of these pathways with losmapimod (a p38 specific inhibitor) and BMS-345541 (a selective NFkB inhibitor) attenuated LPS-induced expression of IL6, TNFα, CCL5, and IL16 mRNA in SnCs. These findings suggest that SnCs may play an important role in the age-related increases in the susceptibility to developing an exacerbated inflammatory response and highlight the potential to use senotherapeutics to ameliorate the severity of various devastating inflammatory conditions in the elderly.
AB - Aging is associated with an increased susceptibility to adverse inflammatory conditions such as sepsis and cytokine storm. We hypothesized that senescent cells (SnCs) play a central role in this age-associated pathology in part due to their expression of the senescence-associated secretory phenotype (SASP), which may prime SnCs to inflammatory stimulation. To test this hypothesis, we examined the expression of various inflammatory cytokines and chemokines at the levels of gene transcription and protein production in various SnCs in vitro in response to lipopolysaccharide (LPS), interleukin-1β (IL1β), and tumor necrosis factor α (TNFα) stimulation. We found that SnCs not only expressed higher basal levels of various inflammatory cytokines and chemokines as a manifestation of the SASP, but more importantly exhibited hyper-activation of the induction of a variety of inflammatory mediators in response to LPS, IL1β and TNFα stimulation as compared with non-SnCs. This senescence-associated hyper-activation is likely mediated in part via the p38MAPK (p38) and NFkB pathways because LPS stimulation elicited significantly higher levels of p38 phosphorylation and NFkB p65 nuclear translation in SnCs when compared to their non-senescent counterparts and inhibition of these pathways with losmapimod (a p38 specific inhibitor) and BMS-345541 (a selective NFkB inhibitor) attenuated LPS-induced expression of IL6, TNFα, CCL5, and IL16 mRNA in SnCs. These findings suggest that SnCs may play an important role in the age-related increases in the susceptibility to developing an exacerbated inflammatory response and highlight the potential to use senotherapeutics to ameliorate the severity of various devastating inflammatory conditions in the elderly.
KW - SASP
KW - cellular senescence
KW - inflammation
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U2 - 10.18632/aging.203396
DO - 10.18632/aging.203396
M3 - Article
C2 - 34375950
AN - SCOPUS:85113283436
SN - 1945-4589
VL - 13
SP - 19088
EP - 19107
JO - Aging
JF - Aging
IS - 15
ER -