Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin

Cristina Zanchi, Carla Zoja, Marina Morigi, Federica Valsecchi, Yan Liu Xue, Daniela Rottoli, Monica Locatelli, Simona Buelli, Anna Pezzotta, Paola Mapelli, Joyce Geelen, Giuseppe Remuzzi, Jacek Hawiger

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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-κB and other stress-responsive transcription factors. Inhibition of their nuclear import with the cellpenetrating SN50 peptide reduced FKN mRNA levels and FKN-mediated leukocyte capture by endothelial cells. Adenoviral overexpression of IκBα 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.

Original languageEnglish
Pages (from-to)1460-1469
Number of pages10
JournalJournal of Immunology
Volume181
Issue number2
Publication statusPublished - Jul 15 2008

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Chemokine CX3CL1
Shiga Toxin
Endothelium
Leukocytes
Endothelial Cells
Hemolytic-Uremic Syndrome
Shiga Toxins
Enterohemorrhagic Escherichia coli
Escherichia coli O157
Cell Nucleus Active Transport
src-Family Kinases
Virulence Factors
Messenger RNA
CX3C Chemokines
Thrombotic Microangiopathies
Shiga-Toxigenic Escherichia coli
Chemotactic Factors
Transcription Factor AP-1
p38 Mitogen-Activated Protein Kinases
Inbred C57BL Mouse

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Zanchi, C., Zoja, C., Morigi, M., Valsecchi, F., Xue, Y. L., Rottoli, D., ... Hawiger, J. (2008). Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. Journal of Immunology, 181(2), 1460-1469.

Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. / Zanchi, Cristina; Zoja, Carla; Morigi, Marina; Valsecchi, Federica; Xue, Yan Liu; Rottoli, Daniela; Locatelli, Monica; Buelli, Simona; Pezzotta, Anna; Mapelli, Paola; Geelen, Joyce; Remuzzi, Giuseppe; Hawiger, Jacek.

In: Journal of Immunology, Vol. 181, No. 2, 15.07.2008, p. 1460-1469.

Research output: Contribution to journalArticle

Zanchi, C, Zoja, C, Morigi, M, Valsecchi, F, Xue, YL, Rottoli, D, Locatelli, M, Buelli, S, Pezzotta, A, Mapelli, P, Geelen, J, Remuzzi, G & Hawiger, J 2008, 'Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin', Journal of Immunology, vol. 181, no. 2, pp. 1460-1469.
Zanchi, Cristina ; Zoja, Carla ; Morigi, Marina ; Valsecchi, Federica ; Xue, Yan Liu ; Rottoli, Daniela ; Locatelli, Monica ; Buelli, Simona ; Pezzotta, Anna ; Mapelli, Paola ; Geelen, Joyce ; Remuzzi, Giuseppe ; Hawiger, Jacek. / Fractalkine and CX3CR1 mediate leukocyte capture by endothelium in response to Shiga toxin. In: Journal of Immunology. 2008 ; Vol. 181, No. 2. pp. 1460-1469.
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