Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on toll-like receptor 4, CD44, and MD-2

Kristen R. Taylor, Kenshi Yamasaki, Katherine A. Radek, Anna Di Nardo, Heidi Goodarzi, Douglas Golenbock, Bruce Beutler, Richard L. Gallo

Research output: Contribution to journalArticle

256 Citations (Scopus)

Abstract

Inflammation under sterile conditions is not well understood despite its importance in trauma and autoimmune disease. To investigate this process we established mouse models of sterile injury and explored the role of hyaluronan in mediating inflammation following injury. The response of cultured monocytes to hyaluronan was different than the response to lipopolysaccharide (LPS) despite both being dependent on Toll-like receptor (TLR4). Cultured cells exposed to hyaluronan showed a pattern of gene induction that mimics the response seen in mouse skin after sterile injury with an increase in molecules such as transforming growth factor-β2 and matrix metalloproteinase-13. These factors were not induced by LPS despite the mutual dependence of both hyaluronan and LPS on TLR4. Explanation for the unique response to hyaluronan was provided by observations that a lack of TLR4 or CD44 in mice diminished the response to sterile injury, and together with MD-2, was required for responsiveness to hyaluronan in vitro. Thus, a unique complex of TLR4, MD-2, and CD44 recognizes hyaluronan. Immunoprecipitation experiments confirmed the physical association of TLR4 and CD44. Taken together, our results define a previously unknown mechanism for initiation of sterile inflammation that involves recognition of released hyaluronan fragments as an endogenous signal of tissue injury.

Original languageEnglish (US)
Pages (from-to)18265-18275
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number25
DOIs
StatePublished - Jun 22 2007

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Toll-Like Receptor 4
Hyaluronic Acid
Wounds and Injuries
Lipopolysaccharides
Inflammation
Matrix Metalloproteinase 13
Toll-Like Receptors
Transforming Growth Factors
Immunoprecipitation
Autoimmune Diseases
Monocytes
Cultured Cells
Skin
Genes
Cells
Tissue
Molecules

ASJC Scopus subject areas

  • Biochemistry

Cite this

Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on toll-like receptor 4, CD44, and MD-2. / Taylor, Kristen R.; Yamasaki, Kenshi; Radek, Katherine A.; Di Nardo, Anna; Goodarzi, Heidi; Golenbock, Douglas; Beutler, Bruce; Gallo, Richard L.

In: Journal of Biological Chemistry, Vol. 282, No. 25, 22.06.2007, p. 18265-18275.

Research output: Contribution to journalArticle

Taylor, Kristen R. ; Yamasaki, Kenshi ; Radek, Katherine A. ; Di Nardo, Anna ; Goodarzi, Heidi ; Golenbock, Douglas ; Beutler, Bruce ; Gallo, Richard L. / Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on toll-like receptor 4, CD44, and MD-2. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 25. pp. 18265-18275.
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