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Bacterial DNA Activates Endothelial Cells and Promotes Neutrophil Adherence through TLR9 Signaling¹

Research Center, Maisonneuve-Rosemont Hospital and Department of Pathology and Cell Biology, University of Montreal, Montreal, Quebec, Canada

TLR9 detects bacterial DNA (CpG DNA) and elicits both innate and adoptive immunity. Recent evidence indicates that TLR9 is expressed in more diverse cell types than initially thought. In this study, we report that HUVECs constitutively express TLR9 and selectively recognize unmethylated CpG motifs in bacterial DNA and synthetic immune stimulatory CpG oligodeoxynucleotides. HUVECs respond to CpG DNA with rapid phosphorylation of IB- and NF-B-mediated gene transcription and surface expression of the adhesion molecules ICAM-1 and E-selectin independent of MAPK signaling. The telomere-derived TLR9 inhibitory oligonucleotide 5'-TTT AGG GTT AGG GTT AGG G-3', agents that block endosomal acidification such as chloroquine and bafilomycin A, and NF-B inhibitors abrogated CpG DNA-induced signaling. HUVEC activation by CpG DNA led to markedly enhanced neutrophil adhesion under nonstatic conditions that was further enhanced when neutrophils were stimulated with CpG DNA. The adhesive interactions were blocked by Abs against CD18 and, to a lesser degree, by anti-E-selectin and anti-L-selectin Abs. Our findings demonstrate that bacterial DNA promotes β₂ integrin and E-selectin-mediated HUVEC-neutrophil adherence, and indicate the ability of CpG DNA to initiate and/or maintain the inflammatory response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant MOP-67054 (to J.G.F.) and a Doctoral Research Award (to J.L.) from the Canadian Institutes of Health Research.

² D.E.K. and L.J. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. János G. Filep, Research Center, Maisonneuve-Rosemont Hospital, 5415 boulevard de l’Assomption, Montreal, Quebec, Canada H1T 2M4. E-mail address: janos.g.filep{at}umontreal.ca

⁴ Abbreviations used in this paper: ODN, oligodeoxynucleotide; iODN, TLR9 inhibitory oligodeoxynucleotide; ctrlODN, control ODN.