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

Area of Science:

• Cell Biology
• Immunology
• Aging Research

Background:

• Extracellular vesicles (EVs) are crucial mediators of intercellular communication, carrying molecular cargo that influences cellular functions.
• The senescence-associated secretory phenotype (SASP) involves the release of EVs (SEVs) that can modulate the tumor microenvironment and systemic inflammation.
• Understanding the immunomodulatory effects of SEVs is critical for deciphering age-related inflammatory processes.

Purpose of the Study:

• To investigate the interaction between EVs from senescent (SEVs) and non-senescent (N-SEVs) fibroblasts with immune cells.
• To determine the impact of SEVs on monocyte activation and inflammatory cytokine production.
• To analyze the molecular differences in cargo between SEVs and N-SEVs and their effect on gene expression.

Main Methods:

• Phagocytosis assays using monocytes, neutrophils, and B cells exposed to SEVs and N-SEVs.
• Lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) production assays in the monocytic THP-1 cell line.
• RNA sequencing and proteomic analysis of THP-1 cells treated with SEVs or N-SEVs.

Main Results:

• SEVs are phagocytosed by monocytes, neutrophils, and B cells via endocytosis.
• SEV pretreatment significantly increases LPS-induced TNF-α production in THP-1 cells (32-66% increase).
• N-SEV treatment decreases TNF-α secretion by THP-1 cells (20% decrease).
• Distinct gene expression profiles and cargo compositions were observed between SEVs and N-SEVs, with SEVs enriching SLITS/ROBO signaling and metabolism pathways.

Conclusions:

• SEVs are recognized and internalized by phagocytes and B cells.
• SEVs promote a pro-inflammatory phenotype in monocytes upon stimulation.
• These findings highlight a potential mechanism by which SEVs contribute to age-related inflammation.