title: Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2.
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 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-beta2 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.
authors.affiliation: Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Taylor
authors.affiliation: Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Yamasaki
authors.affiliation: Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Radek
authors.affiliation: Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161.
authors.forename: Anna Di
authors.initials: AD
authors.lastname: Nardo
authors.affiliation: Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161.
authors.forename: Heidi
authors.initials: H
authors.lastname: Goodarzi
authors.affiliation: Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.affiliation: Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161. Electronic address: rgallo@vapop.ucsd.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D000818:Animals; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D006820:Hyaluronic Acid / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011485:Protein Binding; D012867:Skin / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D018960:Hyaluronan Receptors; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; D053509:Matrix Metalloproteinase 13