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A Toll-like receptor 2–integrin β3 complex senses bacterial lipopeptides via vitronectin

Nature Immunology volume 9, pages 761–768 (2008)Cite this article

Abstract

Toll-like receptor 2 (TLR2) initiates inflammation in response to bacterial lipopeptide (BLP). However, the molecular mechanisms enabling the detection of BLP by TLR2 are unknown. Here we investigated the interaction of BLP with human serum proteins and identified vitronectin as a BLP-recognition molecule. Vitronectin and its receptor, integrin β3, were required for BLP-induced TLR2-mediated activation of human monocytes. Furthermore, monocytes from patients with Glanzmann thrombasthenia, which lack integrin β3, were completely unresponsive to BLP. In addition, integrin β3 formed a complex with TLR2 and this complex dissociated after BLP stimulation. Notably, vitronectin and integrin β3 coordinated responses to other TLR2 agonists such as lipoteichoic acid and zymosan. Our findings show that vitronectin and integrin β3 contribute to the initiation of TLR2 responses.

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Figure 1: Vitronectin from serum binds to BLP and facilitates BLP-induced activation of THP-1 cells.
Figure 2: THP-1 differentiation leads to greater sensitivity to BLP and ITGB3 upregulation.
Figure 3: BLP-induced TNF secretion by THP-1 requires RGD-dependent integrins.
Figure 4: BLP-induced secretion TNF from THP-1 cells requires integrin β3.
Figure 5: Monocytes from patients with Glanzmann thrombasthenia do not respond to BLP.
Figure 6: Integrin β3 forms a complex with TLR2 in unstimulated THP-1 cells.

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Acknowledgements

We thank P. Jungblut and M. Schmidt for mass spectrometry; K. Ray and J. Lambers for experimental help; P. Godowski (Genentech) for anti-TLR2; and the EURIT team for siRNA molecules. Supported by the Deutsche Forschungsgemeinschaft (GraKo 1121 to G.G.) and by the European Union Marie Curie Actions (HPMF-CT-2002-01528 to J.L.d.D.).

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Authors and Affiliations

  1. Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, 10117, Germany

    Gisa Gerold, Arturo Zychlinsky & Juana L de Diego

  2. Department of Peptide Chemistry and Biochemistry, Leibniz Institute for Molecular Pharmacology, Berlin, 13125, Germany

    Khalid Abu Ajaj & Michael Bienert

  3. Department of Pediatric Oncology, Hematology and Immunology, Düsseldorf University Hospital, Düsseldorf, 40225, Germany

    Hans-Jürgen Laws

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  1. Gisa Gerold
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Contributions

G.G. did all experiments unless stated otherwise; K.A.A. and M.B. synthesized the lipopeptides; J.L.d.D. did the BLP precipitation experiments; H.-J.L. was in charge of the patients with Glanzmann thrombasthenia; G.G., A.Z. and J.L.d.D. conceptualized and designed the research and prepared the manuscript; and A.Z. secured the funding.

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Correspondence to Juana L de Diego.

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Gerold, G., Abu Ajaj, K., Bienert, M. et al. A Toll-like receptor 2–integrin β3 complex senses bacterial lipopeptides via vitronectin. Nat Immunol 9, 761–768 (2008). https://doi.org/10.1038/ni.1618

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