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

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 +2 more·2002·The Journal of Experimental Medicine

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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  • ECM-bioscaffold degradation products function as DAMPs that ligate pattern-recognition and scavenger receptors on dendritic cells and macrophages; in some contexts they also signal via integrins.

    “ECM-bioscaffold degradation products function as damage-associated molecular patterns (DAMPs) that ligate pattern-recognition and scavenger receptors on dendritic cells and macrophages; in some contexts, they also signal via integrins [2,26,28,29].”

    From Immune Response to Extracellular Matrix Bioscaffolds: A Comprehensive Review (2025) · cites this paper as [28]

    The Results (no page supplied) show that hyaluronan degradation fragments stimulate dendritic cells through TLR-4, supporting the claim that an extracellular-matrix fragment can signal through a pattern-recognition receptor. The Introduction also reports macrophage activation by hyaluronan fragments. This paper does not establish the broader claim for ECM-bioscaffold degradation products generally, or their signaling through scavenger receptors or integrins. (LLM, conf=0.88)

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Research works printed but not linked: 5

  1. 1998, Lab. Invest., 78, 987
  2. 2000, Chem. Immunol., 74, 61
  3. 1991, Cancer Res., 51, 2524
  4. 1999, Cancer Res., 59, 1287
  5. 1994, Cancer Res., 54, 2419

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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
Venue
The Journal of Experimental Medicine
Published
2002-01-07
Volume
195
Issue
1
Pages
99-111
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W2126659405
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
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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