Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS.
Fragments of hyaluronan released after injury bind and activate TLR4 in a complex with CD44. Here we investigated if the recognition of hyaluronan by CD44 and TLR4 alters lipopolysaccharide (LPS) responsiveness and thus could alter the septic response. In contrast to mice injected with LPS, mice exposed to hyaluronan prior to LPS had greatly decreased serum IL-6 and TNFalpha and were protected from symptoms of sepsis. The protective effect of HA was not seen in Cd44(-/-) mice. Consistent with our findings in vivo, addition of hyaluronan to macrophages before LPS exposure significantly decreased the release of IL-6 and TNFalpha and this effect was not seen in macrophages from Cd44(-/-) mice. Investigation of the mechanism responsible for inhibition of LPS activation showed hyaluronan treatment resulted in an increase in peritoneal macrophage A20 mRNA expression, and that this was significantly reduced in macrophages from Cd44(-/-) mice and Tlr4(-/-) mice. Suppression of the A20 response with siRNA inhibited the ability of hyaluronan to protect against the cytokine response to LPS. Therefore, our results show that hyaluronan acts through TLR4, CD44 and A20 to stimulate a unique cellular response that can protect against the septic response to LPS.
Division of Dermatology, University of California, San Diego and VA San Diego Health Care System, San Diego, CA 92161, USA.
Jun
J
Muto
Kenshi
K
Yamasaki
Kristen R
KR
Taylor
Richard L
RL
Gallo
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D006820:Hyaluronic Acid / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D018805:Sepsis / Q000276:immunology*; D012772:Shock, Septic / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D033942:Adaptor Proteins, Vesicular Transport; D003546:Cysteine Endopeptidases; D016207:Cytokines; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C476286:Ticam1 protein, mouse; C513261:Tnfaip3 protein, mouse