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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7 January 2002
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January 07 2002
Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4
Christian Termeer,
Christian Termeer
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
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Frauke Benedix,
Frauke Benedix
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
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Jonathon Sleeman,
Jonathon Sleeman
2Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
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Christina Fieber,
Christina Fieber
2Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
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Ursula Voith,
Ursula Voith
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
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Thomas Ahrens,
Thomas Ahrens
5Department for Biophysical Chemistry, Biocenter Basel, Basel CH-4056, Switzerland
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Kensuke Miyake,
Kensuke Miyake
4Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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Marina Freudenberg,
Marina Freudenberg
3Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
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Christopher Galanos,
Christopher Galanos
3Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
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Jan Christoph Simon
Jan Christoph Simon
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
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Christian Termeer
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
Frauke Benedix
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
Jonathon Sleeman
2Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
Christina Fieber
2Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
Ursula Voith
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
Thomas Ahrens
5Department for Biophysical Chemistry, Biocenter Basel, Basel CH-4056, Switzerland
Kensuke Miyake
4Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Marina Freudenberg
3Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
Christopher Galanos
3Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
Jan Christoph Simon
1Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany
Address correspondence to C. Termeer, Dept. of Dermatology, University of Freiburg, Hauptstr. 7, D-79104 Freiburg, Germany. Phone: 49-761-270-6831; Fax: 49-761-270-6829; E-mail: [email protected]
*
Abbreviations used in this paper: DC, dendritic cell; HA, Hyaluronic acid; LAL, Limulus amebocyte lysate; MAPK, mitogen-activated protein kinase; PI, phosphatidylinositol; sHA, low-molecular weight oligosaccharides of HA; TLR, Toll-like receptor.
Received:
November 06 2000
Revision Received:
August 28 2001
Accepted:
November 01 2001
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2002
J Exp Med (2002) 195 (1): 99–111.
Article history
Received:
November 06 2000
Revision Received:
August 28 2001
Accepted:
November 01 2001
Citation
Christian Termeer, Frauke Benedix, Jonathon Sleeman, Christina Fieber, Ursula Voith, Thomas Ahrens, Kensuke Miyake, Marina Freudenberg, Christopher Galanos, Jan Christoph Simon; Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4 . J Exp Med 7 January 2002; 195 (1): 99–111. doi: https://doi.org/10.1084/jem.20001858
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