MiR-625-5p is a potential therapeutic target in sepsis by regulating CXCL16/CXCR6 axis and endothelial barrier

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.

CXCL16; CXCR6; Endothelial barrier; Sepsis; miR-625-5p.