Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4.
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.
Termeer
Christian
C
Department of Dermatology, University of Freiburg, Freiburg D-79104, Germany. Termeer@haut.ukl.uni-freiburg.de
Benedix
Frauke
F
Sleeman
Jonathon
J
Fieber
Christina
C
Voith
Ursula
U
Ahrens
Thomas
T
Miyake
Kensuke
K
Freudenberg
Marina
M
Galanos
Christopher
C
Simon
Jan Christoph
JC
D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009844:Oligosaccharides / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009844:Oligosaccharides; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D020928:Mitogen-Activated Protein Kinases