Abstract
Extracellular vesicles (EVs) can be used for intercellular communication by facilitating the transfer of miRNAs from one cell to a recipient cell. MicroRNA (miR)-210-3p is released into the blood during sepsis, inducing cytokine production and promoting leukocyte migration. Thus, the current study aimed to elucidate the role of plasma EVs in delivering miR-210-3p in sepsis-induced acute lung injury (ALI). Plasma EVs were isolated from septic patients, after which the expression of various inflammatory factors was measured using enzyme-linked immunosorbent assay. Cell viability and apoptosis were measured via cell counting kit-8 and flow cytometry. Transendothelial resistance and fluorescein isothiocyanate fluorescence were used to measure endothelial cell permeability. Matrigel was used to examine the tubulogenesis of endothelial cells. The targeting relationship between miR-210-3p and ATG7 was assessed by dual-luciferase reporter assays. The expression of ATG7 and autophagy-related genes was determined to examine autophagic activation. A sepsis mouse model was established by cecal ligation and puncture (CLP)-induced surgery. The level of miR-210-3p was highly enriched in septic EVs. MiR-210-3p enhanced THP-1 macrophage inflammation, BEAS-2B cell apoptosis, and HLMVEC permeability while inhibiting angiogenesis and cellular activity. MiR-210-3p overexpression reduced ATG7 and LC3II/LC3I expression and increased P62 expression. Improvements in vascular density and autophagosome formation, increased ATG7 expression, and changes in the ratio of LC3II/LC3I were detected, as well as reduced P62 expression, in adenovirus-anti-miR-210-3p treated mice after CLP injury. Taken together, the key findings of the current study demonstrate that plasma EVs carrying miR-210-3p target ATG7 to regulate autophagy and inflammatory activation in a sepsis-induced ALI model.
Highlights
Sepsis is characterized by the host inflammatory response to invading pathogens triggering a potentially life-threatening hemodynamic instability, often accompanied by multiple organ dysfunction[1]
In the present study, we aimed to elucidate the role of miR-210-3p in regulating autophagy and inflammatory activation in septic Acute lung injury (ALI) and the intrinsic mechanism, and our results indicated that plasma Extracellular vesicles (EVs)-mediated delivery of miR-210-3p targets Autophagy-related 7 (ATG7) to regulate autophagy and inflammatory activation in sepsis-induced ALI
Our results suggest that the expression of miR-210-3p was increased in the plasma of septic patients and septic mice
Summary
Sepsis is characterized by the host inflammatory response to invading pathogens triggering a potentially life-threatening hemodynamic instability, often accompanied by multiple organ dysfunction[1]. Acute lung injury (ALI) remains one of the most common causes of death in patients suffering from sepsis[2], yet the molecular and cellular mechanisms that drive inflammation, as well as the deterioration of lung function, are not fully understood. The molecular and cellular mechanisms underpinning this condition fail to provide a full picture of sepsis pathogenesis. ALI is characterized by excessive autophagy and inflammation, which often contribute to elevated rates of mortality[5]. Autophagy is a process characterized by cellular engulfment of cytoplasmic proteins or organelles into vesicles, followed by fusion with lysosomes to form autophagic lysosomes and content degradation, and this process has been identified in the induction of sepsis[6].
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