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J. Biol. Chem., Vol. 282, Issue 25, 18265-18275, June 22, 2007

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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^¶, and Richard L. Gallo¹

From the Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161, the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, and the ^¶Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

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 4 (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-2 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.

Received for publication, July 3, 2006 , and in revised form, March 28, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1.

¹ To whom correspondence should be addressed: Division of Dermatology, University of California, MC 9111B, 3350 La Jolla Village Dr., San Diego, CA 92161. Tel.: 858-642-3504; Fax: 858-642-1435; E-mail: rgallo{at}vapop.ucsd.edu.

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