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Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4

  • Termeer, Christian Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
  • Benedix, Frauke Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
  • Sleeman, Jonathon Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
  • Fieber, Christina Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
  • Voith, Ursula Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
  • Ahrens, Thomas Department for Biophysical Chemistry, Biocenter Basel, Basel CH-4056, Switzerland
  • Miyake, Kensuke Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
  • Freudenberg, Marina Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
  • Galanos, Christopher Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
  • Simon, Jan Christoph Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
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  • 2002-1-7
Published in:
  • Journal of Experimental Medicine. - Rockefeller University Press. - 2002, vol. 195, no. 1, p. 99-111
Immunology
Immunology and Allergy
English Low molecular weight fragmentation products of the polysaccharide of Hyaluronic acid (sHA) produced during inflammation have been shown to be potent activators of immunocompetent cells such as dendritic cells (DCs) and macrophages. Here we report that sHA induces maturation of DCs via the Toll-like receptor (TLR)-4, a receptor complex associated with innate immunity and host defense against bacterial infection. Bone marrow–derived DCs from C3H/HeJ and C57BL/10ScCr mice carrying mutant TLR-4 alleles were nonresponsive to sHA-induced phenotypic and functional maturation. Conversely, DCs from TLR-2–deficient mice were still susceptible to sHA. In accordance, addition of an anti–TLR-4 mAb to human monocyte–derived DCs blocked sHA-induced tumor necrosis factor α production. Western blot analysis revealed that sHA treatment resulted in distinct phosphorylation of p38/p42/44 MAP-kinases and nuclear translocation of nuclear factor (NF)-κB, all components of the TLR-4 signaling pathway. Blockade of this pathway by specific inhibitors completely abrogated the sHA-induced DC maturation. Finally, intravenous injection of sHA-induced DC emigration from the skin and their phenotypic and functional maturation in the spleen, again depending on the expression of TLR-4. In conclusion, this is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.
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  • English
Open access status
bronze
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https://folia.unifr.ch/global/documents/225306
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