Impact of Senescent Cell‐Derived Extracellular Vesicles on Innate Immune Cell Function

Abstract Extracellular vesicles (EVs) are components of the senescence‐associated secretory phenotype (SASP) that influence cellular functions via their cargo. Here, the interaction between EVs derived from senescent (SEVs) and non‐senescent (N‐SEVs) fibroblasts and the immune system is investigated. Via endocytosis, SEVs are phagocytosed by monocytes, neutrophils, and B cells. Studies with the monocytic THP‐1 cell line find that pretreatment with SEVs results in a 32% ( p < 0.0001) and 66% ( p < 0.0001) increase in lipopolysaccharide (LPS)‐induced tumor necrosis factor‐alpha (TNF‐α) production when compared to vehicle control or N‐SEVs respectively. Interestingly, relative to vehicle control, THP‐1 cells exposed to N‐SEVs exhibit a 20% decrease in TNF‐α secretion ( p < 0.05). RNA sequencing reveals significant differences in gene expression in THP‐1 cells treated with SEVs or N‐SEVs, with vesicle‐mediated transport and cell cycle regulation pathways featuring predominantly with N‐SEV treatment, while pathways relating to SLITS/ROBO signaling, cell metabolism, and cell cycle regulation are enriched in THP‐1 cells treated with SEVs. Proteomic analysis also reveals significant differences between SEV and N‐SEV cargo. These results demonstrate that phagocytes and B cells uptake SEVs and drive monocytes toward a more proinflammatory phenotype upon LPS stimulation. SEVs may therefore contribute to the more proinflammatory immune response seen with aging.