Senescence-associated hyper-activation to inflammatory stimuli in vitro

Vivekananda Budamagunta, Sahana Manohar-Sindhu, Yang Yang, Yonghan He, Dmitry O. Traktuev, Thomas C. Foster, Daohong Zhou

Producción científica: Articlerevisión exhaustiva

23 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)19088-19107
Número de páginas20
PublicaciónAging
Volumen13
N.º15
DOI
EstadoPublished - 2021
Publicado de forma externa

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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