Cited by 1,378Immune Response and InflammationProteoglycans and glycosaminoglycans researchImmunotherapy and Immune Responses

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

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Termeer, Christian, Benedix, Frauke, Sleeman, Jonathon, Fieber, Christina, Voith, Ursula, Ahrens, Thomas, Miyake, Kensuke, Freudenberg, Marina, Galanos, Christopher, Simon, Jan Christoph·2002·The Journal of Experimental Medicine

DOI 10.1084/jem.20001858PMC PMC2196009

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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 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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Authors: Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., Miyake, K., Freudenberg, M., Galanos, C., & Simon, J. C.
Affiliations: University of Freiburg (DE)
2Institute for Genetics, Forschungszentrum Karlsruhe, Karlsruhe D-76021, Germany
University of Basel (CH)
Institute of Medical Science, The University of Tokyo (JP)
Max Planck Society (DE)
3Max-Planck Institute for Immunobiology, Freiburg D-79011, Germany
ORCID: Miyake, Kensuke
Freudenberg, Marina
Simon, Jan Christoph
Venue: The Journal of Experimental Medicine
Publisher: Rockefeller University Press
Published: 2002-01-07
Volume: 195
Issue: 1
Pages: 99-111
ISSN: 0022-1007 (ISSN-L)
1540-9538
DOI: 10.1084/jem.20001858
PMC: PMC2196009
OpenAlex: W2126659405
Semantic Scholar: 44579905bd40557fb010b65248e3194bbd6a995d
Cited by: 1,378
References: 48
Citations by year: 2026: 19 · 2025: 29 · 2024: 28 · 2023: 28 · 2022: 32 · 2021: 54 · 2020: 46 · 2019: 40 · 2018: 40 · 2017: 41 · 2016: 54 · 2015: 59 · 2014: 71 · 2013: 61 · 2012: 69
FWCI: 18.95
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: cc-by-nc-sa
Locations: The Journal of Experimental Medicine (publishedVersion)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Max Planck Digital Library (submittedVersion)
FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: hyaluronic acid, oligosaccharides, dendritic cell maturation, TLR4, TLR2, innate immunity, endogenous ligands, MAPK signaling, TNF-α, extracellular matrix degradation, inflammation
MeSH terms: Animals, Cell Differentiation, Dendritic Cells, Female, Humans, Hyaluronic Acid, Membrane Glycoproteins, Mice, Inbred C3H, Mice, Inbred C57BL, Oligosaccharides, Receptors, Cell Surface, Tumor Necrosis Factor-alpha, Signal Transduction, Down-Regulation, NF-kappa B, Mitogen-Activated Protein Kinases, Drosophila Proteins, Toll-Like Receptors, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice

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

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