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Plasma extracellular vesicle-derived miR-296-5p is a maturation-dependent rejuvenation factor that downregulates inflammation and improves survival after sepsis

ABSTRACT: There is a progressive decline in physiological function with age, and aging is associated with increased susceptibility to injury and infection. However, several reports have indicated that the agility of youth is characterized by transferable rejuvenating molecular factors, as was observed previously in heterochronic parabiosis experiments. These experiments demonstrated a rejuvenating effect of young blood in old animals. There have been several efforts to characterize these youthful or maturation-associated factors in the young blood. In this report, we demonstrate the resilience of young mice, at or before puberty, to polymicrobial sepsis and show an age-dependent effect of plasma extracellular vesicles on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti-inflammatory, and reduced cellular senescence markers. MicroRNA sequencing of the extracellular vesicles showed an age-associated signature and identified miR-296-5p and miR-541-5p to progressively reduce their levels in the blood plasma with increasing age. We further show that the levels of these miRNAs decline with age in multiple organs. The miRNAs miR-296-5p and miR-541-5p showed a reparatory effect in an in vitro wound healing model and the miR-296-5p, when given intraperitoneally, reduced mortality in the mouse model of sepsis. In summary, our studies demonstrate that EVs from very young mice have a reparative effect on sepsis, and the reparative factors are likely maturation-dependent. Our observation that miR-296-5p and miR-541-5p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these miRNAs in inflammation and age-associated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE300900 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Sepsis remains a leading cause of death and currently has no pathogenesis-specific therapy. Hampered progress is partly due to the lack of insight into deep mechanistic processes. Deciphering the functions of microRNAs in sepsis pathogeny became a dynamic research topic in the last decade. To screen for new microRNA targets for sepsis therapeutics, we used human samples: microRNA array data from peripheral blood mononuclear cells (PBMCs) from sepsis patients and controls, whole blood samples from sepsis survivors; and multiple animal models: mouse cecum ligation-puncture (CLP)-induced sepsis, mouse viral microRNA challenge, and baboon Gram-positive and Gram-negative sepsis models. miR-93-5p met the criteria for a therapeutic target, being overexpressed in baboons which died early after induction of sepsis and downregulated in humans who survived after sepsis. Therapeutically, inhibiting miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in old mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially CD4+ subset. Ago2-immunoprecipitation in miR-93-knockout T cells identified important regulatory receptors, CD28 and CD160, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis in the elderly through its regulation of both innate and adaptive immunity. We applied the Ago2-RIP Chip (Ribonucleoprotein ImmunoPrecipitation followed by microarray analysis) to identify miR-93-5p target mRNAs. This methodology uses beads coupled to either anti-Ago2 antibody (or an IgG control) to pull down the RISC complex together with any miRNA-interacting mRNAs. To define target genes of miR-93-5p, we assessed mRNA transcripts enriched in the Ago2-IP fraction of JURKAT parental cells or control cells (where miR-93-5p is present) but not in the two KO clones (where miR-93-5p is absent) by microarray

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Plasma extracellular vesicle-derived miR-296-5p is a maturation-dependent rejuvenation factor that downregulates inflammation and improves survival after sepsis

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