Synergistic enhancement of Toll-like receptor responses by NOD1 activation

Authors

  • David A. van Heel,

    Corresponding author
    1. Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London (Hammersmith Campus), London, UK
    • Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London, Hammersmith Campus, London, W12 0NN, UK
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  • Subrata Ghosh,

    1. Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London (Hammersmith Campus), London, UK
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  • Matt Butler,

    1. Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London (Hammersmith Campus), London, UK
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  • Karen Hunt,

    1. Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London (Hammersmith Campus), London, UK
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  • Brian Michael J. Foxwell,

    1. Kennedy Institute of Rheumatology, Imperial College London, Aspenlea Road, London, UK
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  • Dominique Mengin-Lecreulx,

    1. Enveloppes Bactériennes et Antibiotiques, Institut de Biochimie et Biophysique Moléculaire et Cellulaire,Unité Mixte de Recherche 8619 CNRS, Université Paris-Sud, Paris, France
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  • Raymond J. Playford

    1. Intestinal Inflammation and Repair Group, Department of Gastroenterology, Imperial College London (Hammersmith Campus), London, UK
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Abstract

NOD1 is an intracellular pattern-recognition receptor specific for Gram-negative peptidoglycan that is important in host response to infections (e.g. Helicobacter pylori and Shigella flexneri). Genetic variation in NOD1 predisposes to asthma and inflammatory bowel disease. Functional responses have not previously been studied in primary human cells. NOD1 activation by low nanomolar concentrations of the specific muropeptide ligand M-TriDAP induced minimal human peripheral blood mononuclear cell TNF-α, IL-1β or IL-10 secretion, but synergistically increased Toll-like receptor (TLR)-induced responses. Synergistic responses were seen across multiple ligands (to TLR1/2, 2/6, 4, 5, 7/8) and a broad range of cytokine secretion (TNF-α, IL-1α, IL-1β, IL-4, IL-6, IL-10, GM-CSF). Synergy was also observed in the allogeneic mixed lymphocyte reaction. These responses were similar in cells homozygous for Crohn's disease-associated NOD2 mutations. In contrast to cell lines, primary human peripheral blood mononuclear cells respond to NOD1 muropeptides at ∼ 100-fold lower concentrations. Cross-talk between cytosolic NOD1 and membrane-bound TLR enhances responses to the multiple antigens simultaneously presented by a microbe.

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