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Abstract
Escherichia coli, as one of the gut microbiota, can evoke severe inflammatory diseases including peritonitis and sepsis. Gram-negative bacteria including E. coli constitutively release nano-sized outer membrane vesicles (OMVs). Although E. coli OMVs can induce the inflammatory responses without live bacteria, the effect of E. coli OMVs in vivo on endothelial cell function has not been previously elucidated. In this study, we show that bacteria-free OMVs increased the expression of endothelial intercellular adhesion molecule-1 (ICAM-1), E-selectin and vascular cell adhesion molecule-1, and enhanced the leukocyte binding on human microvascular endothelial cells in vitro. Inhibition of NF-κB and TLR4 reduced the expression of cell adhesion molecules in vitro. OMVs given intraperitoneally to the mice induced ICAM-1 expression and neutrophil sequestration in the lung endothelium, and the effects were reduced in ICAM-1-/- and TLR4-/- mice. When compared to free lipopolysaccharide, OMVs were more potent in inducing both ICAM-1 expression as well as leukocyte adhesion in vitro, and ICAM-1 expression and neutrophil sequestration in the lungs in vivo. This study shows that OMVs potently up-regulate functional cell adhesion molecules via NF-κB- and TLR4-dependent pathways, and that OMVs are more potent than free lipopolysaccharide.
Highlights
Endothelial cells cover an area of 4,000 to 7,000 m2 of the human body [1], and can respond directly to bacterial infection, leading to local recruitment of leukocytes into the infected tissue [2,3]
The addition of bacteria-free outer membrane vesicles (OMVs) derived from E. coli (10 or 100 ng/mL in total protein) significantly increased the expression of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells (HMVECs) (Figure 1A)
Treatment of BAY11-7082 (1 mM) almost completely inhibited the leukocyte adhesion to OMV-treated endothelial cells (Figure 1G). These results clearly indicate that E. coli OMVs upregulate functional ICAM-1, E-selectin, or VCAM-1 expression in endothelial cells via the activation of NF-kB
Summary
Endothelial cells cover an area of 4,000 to 7,000 m2 of the human body [1], and can respond directly to bacterial infection, leading to local recruitment of leukocytes into the infected tissue [2,3]. The addition of bacteria-free OMVs derived from E. coli (10 or 100 ng/mL in total protein) significantly increased the expression of ICAM-1, E-selectin, and VCAM-1 in HMVECs (Figure 1A).
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