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Abstract
Outer membrane vesicles (OMVs) are spherical, proteolipid nanostructures that are constitutively released by Gram-negative bacteria including Escherichia coli. Although it has been shown that administration of E. coli OMVs stimulates a strong pulmonary inflammatory response with infiltration of neutrophils into the lungs in vivo, the mechanism of E. coli OMV-mediated neutrophil recruitment is poorly characterized. In this study, we observed significant infiltration of neutrophils into the mouse lung tissues in vivo, with increased expression of the neutrophil chemoattractant CXCL1, a murine functional homolog of human IL-8, on intraperitoneal administration of E. coli OMVs. In addition, OMVs and CD31-positive endothelial cells colocalized in the mouse lungs. Moreover, in vitro results showed that E. coli OMVs significantly increased IL-8 release from human microvascular endothelial cells and toll-like receptor (TLR)4 was found to be the main component for recognizing E. coli OMVs among human endothelial cell-associated TLRs. Furthermore, the transmigration of neutrophils was suppressed in the lung tissues obtained from TLR4 knockout mice treated with E. coli OMVs. Taken together, our data demonstrated that E. coli OMVs potently recruit neutrophils into the lung via the release of IL-8/CXCL1 from endothelial cells in TLR4- and NF-κB-dependent manners.
Highlights
Escherichia coli and other Gram-negative bacteria are normal flora in the human colon, they can induce sepsis through robustly activating the host immune system (Costerton et al, 1974; Annane et al, 2005; O’Hara and Shanahan, 2006)
Our results demonstrated that E. coli Outer membrane vesicles (OMVs)-induced neutrophil transmigration in the lungs was associated with the increased release of CXCL1 in the Bronchoalveolar lavage (BAL) fluid as a consequence of treatment with OMVs
We have previously demonstrated that E. coli OMVs induce neutrophilic inflammation in the lungs (Park et al, 2010; Jang et al, 2015) and upregulate the expression of cell adhesion molecules in the lung endothelium (Kim J.H. et al, 2013)
Summary
Escherichia coli and other Gram-negative bacteria are normal flora in the human colon, they can induce sepsis through robustly activating the host immune system (Costerton et al, 1974; Annane et al, 2005; O’Hara and Shanahan, 2006). Sepsis-involved Gram-negative bacteria, such as E. coli, Pseudomonas aeruginosa, and Acinetobacter baumannii, can secrete outer membrane vesicles (OMVs) (Lee et al, 2007; Kwon et al, 2009; Park et al, 2010; Choi et al, 2011). OMVs elicit host immune responses by activating several sentinel cells and inducing the release of cytokines/chemokines, further promoting recruitment of inflammatory cells to the inflamed tissues (Zhang et al, 1997; Opal, 2007). E. coli OMVs induce dysfunction of the lungs by attracting leukocytes, especially neutrophils, and increasing lung permeability and the release of cytokines in the lung tissues (Park et al, 2010; Kim J.H. et al, 2013). Attracted by chemokines, circulating neutrophils first adhere to the endothelium and transmigrate out of the vasculature into the interstitial tissues (Smith et al, 1991)
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