MiR-625-5p is a potential therapeutic target in sepsis by regulating CXCL16/CXCR6 axis and endothelial barrier
Xiao Huang1, Yuxin Fei1, Xiaoyu Qiu2
1Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China.
Background:
MicroRNA plays an important role in the progression of sepsis. We found a significant increase of in miR-625-5p expression in the blood of patients with sepsis, and lipopolysaccharide (LPS)-stimulated EA.hy926 cells. To date, little is known about the specific biological function of miR-625-5p in sepsis.
Methods:
Changes in miR-625-5p expression were verified through quantitative real-time polymerase chain reaction in 45 patients with sepsis or septic shock and 30 healthy subjects. In vitro, EA.hy926 cells were treated with LPS. Transendothelial electrical resistance assay and FITC-dextran were used in evaluating endothelial barrier function.
Results:
Herein, patients with sepsis or septic shock had significantly higher miR-625-5p expression levels, chemokine (C-X-C motif) ligand 16 (CXCL16) levels, and glycocalyx components than the healthy controls, and miR-625-5p level was positively correlated with disease. Kaplan-Meier analysis demonstrated a strong association between miR-625-5p level and 28-day mortality. Furthermore, the miR-625-5p inhibitor significantly alleviated LPS-induced endothelial barrier injury in vitro. Then, miR-625-5p positively regulated CXCL16 and down-regulated miR-625-5p attenuated CXCL16 transcription and expression in EA.hy926 cells. CXCL16 knockout significantly alleviated vascular barrier dysfunction in the LPS-induced EA.hy926 cells. sCXCL16 treatment in EA.hy926 cells significantly increased endothelial hyperpermeability by disrupting endothelial glycocalyx, tight junction proteins, and adherens junction proteins through the modulation of C-X-C chemokine receptor type 6 (CXCR6).
Conclusions:
Increase in miR-625-5p level may be an effective biomarker for predicting 28-day mortality in patients with sepsis/septic shock. miR-625-5p is a critical pathogenic factor for endothelial barrier dysfunction in LPS-induced EA.hy926 cells because it activates the CXCL16/CXCR6 axis.
Insights
Elevated miR-625-5p levels in sepsis patients correlate with increased mortality. This microRNA drives endothelial barrier dysfunction by activating the CXCL16/CXCR6 pathway, offering a potential biomarker for sepsis prognosis.
Area of Science:
- Molecular Biology
- Sepsis Pathophysiology
- Biomarker Discovery
Background:
- MicroRNAs (miRNAs) are crucial in sepsis progression.
- miR-625-5p expression is significantly elevated in sepsis patients and lipopolysaccharide (LPS)-stimulated cells.
- The precise role of miR-625-5p in sepsis remains largely undefined.
Purpose of the Study:
- To investigate the role of miR-625-5p in sepsis pathogenesis.
- To explore miR-625-5p as a potential biomarker for sepsis-related mortality.
- To elucidate the molecular mechanisms underlying miR-625-5p's effect on endothelial barrier function.
Main Methods:
- Quantitative real-time polymerase chain reaction (qRT-PCR) to measure miR-625-5p expression in 45 sepsis patients and 30 healthy controls.
- In vitro studies using EA.hy926 cells treated with LPS to assess endothelial barrier function via transendothelial electrical resistance and FITC-dextran assays.
- Analysis of miR-625-5p, CXCL16, and glycocalyx component levels, correlation with disease severity and mortality, and investigation of the CXCL16/CXCR6 axis.
Main Results:
- Sepsis patients exhibited significantly higher miR-625-5p, CXCL16, and glycocalyx component levels compared to healthy controls.
- miR-625-5p levels positively correlated with disease severity and 28-day mortality.
- In vitro, miR-625-5p inhibition ameliorated LPS-induced endothelial barrier injury, while CXCL16 activation exacerbated it by disrupting tight junctions and glycocalyx via the CXCR6 pathway.
Conclusions:
- Elevated miR-625-5p serves as a potential biomarker for predicting 28-day mortality in sepsis/septic shock.
- miR-625-5p is a key pathogenic factor in sepsis-induced endothelial barrier dysfunction.
- The miR-625-5p/CXCL16/CXCR6 axis plays a critical role in the pathogenesis of sepsis-related endothelial barrier impairment.
