Chen Yung-Yi, Sullivan Jack, Hanley Shaun, Price Joshua, Tariq Mohammad A, McIlvenna Luke C, Whitham Martin, Sharma-Oates Archana, Harrison Paul, Lord Janet M, Hazeldine Jon
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK.
Scar Free Foundation Centre for Conflict Wound Research, University Hospitals Birmingham, Birmingham, B15 2GW, UK.
Adv Biol (Weinh). 2024 Dec;8(12):e2400265. doi: 10.1002/adbi.202400265. Epub 2024 Oct 23.
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.
细胞外囊泡（EVs）是衰老相关分泌表型（SASP）的组成部分，可通过其携带的物质影响细胞功能。在此，研究了衰老成纤维细胞来源的EVs（SEVs）与非衰老成纤维细胞来源的EVs（N-SEVs）和免疫系统之间的相互作用。通过内吞作用，SEVs被单核细胞、中性粒细胞和B细胞吞噬。对单核细胞系THP-1细胞的研究发现，与溶剂对照或N-SEVs相比，用SEVs预处理分别导致脂多糖（LPS）诱导的肿瘤坏死因子-α（TNF-α）产生增加32%（p<0.0001）和66%（p<0.0001）。有趣的是，相对于溶剂对照，暴露于N-SEVs的THP-1细胞TNF-α分泌减少20%（p<0.05）。RNA测序揭示了用SEVs或N-SEVs处理的THP-1细胞中基因表达的显著差异，N-SEV处理主要以囊泡介导的转运和细胞周期调控途径为特征，而与SLITS/ROBO信号传导、细胞代谢和细胞周期调控相关途径在用SEVs处理的THP-1细胞中富集。蛋白质组学分析也揭示了SEV和N-SEV携带物质之间的显著差异。这些结果表明，吞噬细胞和B细胞摄取SEVs，并在LPS刺激下促使单核细胞向更具促炎表型发展。因此，SEVs可能导致衰老时出现更具促炎的免疫反应。
