Outer Membrane Vesicles Derived from Escherichia coli Up-Regulate Expression of Endothelial Cell Adhesion Molecules In Vitro and In Vivo

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.

Immune modulation by bacterial outer membrane vesicles

“…52), tissue factor, thrombomodulin, and the adhesion molecules P-selectin and E-selectin 53 by human endothelial cells, which leads to the recruitment of proinflammatory leukocytes, platelet aggregation and coagulation 52 . Similarly, E. coli OMVs upregulate the expression of E-selectin, ICAM1 and vascular cell adhesion molecule 1 (VCAM1) on the surface of human microvascular endothelial cells 54 . When administered intraperitoneally to mice, these OMVs induce neutrophil aggregation in the lung endothelium in an ICAM1-and TLR4-dependent manner, suggesting that OMVs are used by pathogens to sequester leukocytes in the endothelium 54 .…”

The Future of Vascular Biology and Medicine

“…When endothelial cells are exposed to these vesicles, they demonstrate an acute inflammatory response by upregulating expression of the endothelial cell adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. 44 …”

Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation

“…Therefore, OMV, similar to eukaryotic exosomes/microvesicles, are an efficient inter-cellular communication mechanism (Demuth et al, 2003; Galka et al, 2008; Kesty et al, 2004). Previous studies showed that purified OMV are immunostimulatory (Kim et al, 2013; Park et al, 2010), and OMV-associated peptidoglycan has been shown to activate NOD signaling and NF-κB activation (Bonham and Kagan, 2014; Kaparakis et al, 2010). Furthermore, OMV produced by gut microbiota play an immunomodulatory role in mucosal immunity (Hickey et al, 2015; Shen et al, 2012).…”