Hyaluronan fragments act as an endogenous danger signal by engaging TLR2.
Upon tissue injury, high m.w. hyaluronan (HA), a ubiquitously distributed extracellular matrix component, is broken down into lower m.w. (LMW) fragments, which in turn activate an innate immune response. In doing so, LMW HA acts as an endogenous danger signal alerting the immune system of a breach in tissue integrity. In this report, we demonstrate that LMW HA activates the innate immune response via TLR-2 in a MyD88-, IL-1R-associated kinase-, TNFR-associated factor-6-, protein kinase Czeta-, and NF-kappaB-dependent pathway. Furthermore, we show that intact high m.w. HA can inhibit TLR-2 signaling. Finally, we demonstrate that LMW HA can act as an adjuvant promoting Ag-specific T cell responses in vivo in wild-type but not TLR-2(null) mice.
Scheibner
Kara A
KA
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore, MD 21205, USA.
Lutz
Michael A
MA
Boodoo
Sada
S
Fenton
Matthew J
MJ
Powell
Jonathan D
JD
Horton
Maureen R
MR
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008970:Molecular Weight; D053594:Myeloid Differentiation Factor 88; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D000099221:Protein Kinase C zeta
D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D006820:Hyaluronic Acid; D018836:Inflammation Mediators; D007527:Isoenzymes; D053594:Myeloid Differentiation Factor 88; D011493:Protein Kinase C; D051195:Toll-Like Receptor 2; D000099221:Protein Kinase C zeta; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; C493486:Tlr2 protein, mouse