Fractalkine and CX3CR1 Mediate Leukocyte Capture by Endothelium in Response to Shiga Toxin
| Autor: | Marina Morigi, Daniela Rottoli, Anna Pezzotta, Federica Valsecchi, Cristina Zanchi, Paola Mapelli, Giuseppe Remuzzi, Joyce Geelen, Xue Yan Liu, Simona Buelli, Carla Zoja, Jacek Hawiger, Monica Locatelli |
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| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
Male Chemokine Thrombotic microangiopathy Endothelium Kidney Glomerulus Immunology CX3C Chemokine Receptor 1 Escherichia coli O157 Shiga Toxin 2 p38 Mitogen-Activated Protein Kinases Mice Metabolism transport and motion [NCMLS 2] CX3CR1 Cell Adhesion Leukocytes medicine Animals Humans Immunology and Allergy Cell adhesion Cells Cultured biology Chemokine CX3CL1 NF-kappa B Endothelial Cells Shiga toxin medicine.disease Up-Regulation Cell biology Mice Inbred C57BL Transcription Factor AP-1 Disease Models Animal medicine.anatomical_structure Hemolytic-Uremic Syndrome biology.protein Receptors Chemokine Signal transduction Tyrosine kinase Signal Transduction |
| Zdroj: | Journal of Immunology, 181, 2, pp. 1460-9 Europe PubMed Central Journal of Immunology, 181, 1460-9 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.181.2.1460 |
| Popis: | Contains fulltext : 70248.pdf (Publisher’s version ) (Closed access) Shiga toxins (Stx) are the virulence factors of enterohemorrhagic Escherichia coli O157:H7, a worldwide emerging diarrheal pathogen, which precipitates postdiarrheal hemolytic uremic syndrome, the leading cause of acute renal failure in children. In this study, we show that Stx2 triggered expression of fractalkine (FKN), a CX3C transmembrane chemokine, acting as both adhesion counterreceptor on endothelial cells and soluble chemoattractant. Stx2 caused in HUVEC expression of FKN mRNA and protein, which promoted leukocyte capture, ablated by Abs to either endothelial FKN or leukocyte CX3CR1 receptor. Exposure of human glomerular endothelial cells to Stx2 recapitulated its FKN-inducing activity and FKN-mediated leukocyte adhesion. Both processes required phosphorylation of Src-family protein tyrosine kinase and p38 MAPK in endothelial cells. Furthermore, they depended on nuclear import of NF-kappaB and other stress-responsive transcription factors. Inhibition of their nuclear import with the cell-penetrating SN50 peptide reduced FKN mRNA levels and FKN-mediated leukocyte capture by endothelial cells. Adenoviral overexpression of IkappaBalpha inhibited FKN mRNA up-regulation. The FKN-mediated responses to Stx2 were also dependent on AP-1. In mice, both virulence factors of Stx-producing E. coli, Stx and LPS, are required to elicit hemolytic uremic syndrome. In this study, FKN was detected within glomeruli of C57BL/6 mice injected with Stx2, and further increased after Stx2 plus LPS coadministration. This was associated with recruitment of CX3CR1-positive cells. Thus, in response to Stx2, FKN is induced playing an essential role in the promotion of leukocyte-endothelial cell interaction thereby potentially contributing to the renal microvascular dysfunction and thrombotic microangiopathy that underlie hemolytic uremic syndrome due to enterohemorrhagic E. coli O157:H7 infection. |
| Databáze: | OpenAIRE |
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