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PMID: 11781369 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4.

The Journal of experimental medicine ·Vol. 195 ·No. 1 ·2002-01-07 ·Pages 99-111

Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC

Abstract

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 alpha 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)-kappa B, 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.

MeSH Terms
Animals Cell Differentiation Dendritic Cells/immunology Down-Regulation Drosophila Proteins Female Humans Hyaluronic Acid/immunology Membrane Glycoproteins/deficiency,metabolism Mice Mice, Inbred C3H Mice, Inbred C57BL Mitogen-Activated Protein Kinases/metabolism NF-kappa B/metabolism Oligosaccharides/immunology Receptors, Cell Surface/deficiency,metabolism Signal Transduction Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors Tumor Necrosis Factor-alpha/metabolism
Chemicals
Drosophila Proteins Membrane Glycoproteins NF-kappa B Oligosaccharides Receptors, Cell Surface TLR2 protein, human TLR4 protein, human Toll-Like Receptor 2 Toll-Like Receptor 4 Toll-Like Receptors Tumor Necrosis Factor-alpha Hyaluronic Acid Mitogen-Activated Protein Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Termeer Christian
Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany. [email protected]
Benedix Frauke
Sleeman Jonathon
Fieber Christina
Voith Ursula
Ahrens Thomas
Miyake Kensuke
Freudenberg Marina
Galanos Christopher
Simon Jan Christoph
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20001858
Email
[email protected]
Published
2002-01-07
Pages
99-111
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2196009
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20001858 PMC Full Text View journal details
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