Taylor Kristen R, Yamasaki Kenshi, Radek Katherine A, Nardo Anna Di, Goodarzi Heidi, Golenbock Douglas, Beutler Bruce, Gallo Richard L
Division of Dermatology, University of California, San Diego and Veterans Affairs Medical Center, San Diego, California 92161.
Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
J Biol Chem. 2007 Jun 22;282(25):18265-18275. doi: 10.1074/jbc.M606352200. Epub 2007 Mar 30.
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.
尽管无菌条件下的炎症在创伤和自身免疫性疾病中具有重要意义，但人们对此尚未完全了解。为了研究这一过程，我们建立了无菌损伤小鼠模型，并探讨了透明质酸在介导损伤后炎症中的作用。尽管培养的单核细胞对透明质酸和脂多糖（LPS）的反应均依赖于Toll样受体4（TLR4），但其对透明质酸的反应与对LPS的反应不同。暴露于透明质酸的培养细胞表现出一种基因诱导模式，类似于无菌损伤后小鼠皮肤中的反应，其中转化生长因子-β2和基质金属蛋白酶-13等分子增加。尽管透明质酸和LPS都依赖于TLR4，但LPS不会诱导这些因子。小鼠缺乏TLR4或CD44会减弱对无菌损伤的反应，且在体外对透明质酸的反应需要TLR4、MD-2和CD44共同存在，这些观察结果为对透明质酸的独特反应提供了解释。因此，TLR4、MD-2和CD44形成的独特复合物可识别透明质酸。免疫沉淀实验证实了TLR4与CD44的物理结合。综上所述，我们的结果确定了一种先前未知的无菌炎症起始机制，该机制涉及将释放的透明质酸片段识别为组织损伤的内源性信号。
