Muto Jun, Yamasaki Kenshi, Taylor Kristen R, Gallo Richard L
Division of Dermatology, University of California, San Diego and VA San Diego Health Care System, San Diego, CA 92161, USA.
Mol Immunol. 2009 Dec;47(2-3):449-56. doi: 10.1016/j.molimm.2009.08.026. Epub 2009 Sep 24.
Fragments of hyaluronan released after injury bind and activate TLR4 in a complex with CD44. Here we investigated if the recognition of hyaluronan by CD44 and TLR4 alters lipopolysaccharide (LPS) responsiveness and thus could alter the septic response. In contrast to mice injected with LPS, mice exposed to hyaluronan prior to LPS had greatly decreased serum IL-6 and TNFalpha and were protected from symptoms of sepsis. The protective effect of HA was not seen in Cd44(-/-) mice. Consistent with our findings in vivo, addition of hyaluronan to macrophages before LPS exposure significantly decreased the release of IL-6 and TNFalpha and this effect was not seen in macrophages from Cd44(-/-) mice. Investigation of the mechanism responsible for inhibition of LPS activation showed hyaluronan treatment resulted in an increase in peritoneal macrophage A20 mRNA expression, and that this was significantly reduced in macrophages from Cd44(-/-) mice and Tlr4(-/-) mice. Suppression of the A20 response with siRNA inhibited the ability of hyaluronan to protect against the cytokine response to LPS. Therefore, our results show that hyaluronan acts through TLR4, CD44 and A20 to stimulate a unique cellular response that can protect against the septic response to LPS.
损伤后释放的透明质酸片段与CD44形成复合物，结合并激活Toll样受体4（TLR4）。在此，我们研究了CD44和TLR4对透明质酸的识别是否会改变脂多糖（LPS）反应性，进而改变脓毒症反应。与注射LPS的小鼠相比，在注射LPS前接触透明质酸的小鼠血清白细胞介素-6（IL-6）和肿瘤坏死因子α（TNFα）大幅降低，且免受脓毒症症状的影响。在Cd44基因敲除（Cd44(-/-)）小鼠中未观察到透明质酸的保护作用。与我们在体内的研究结果一致，在LPS刺激前向巨噬细胞中添加透明质酸可显著降低IL-6和TNFα的释放，而在Cd44(-/-)小鼠的巨噬细胞中未观察到这种作用。对负责抑制LPS激活的机制进行研究发现，透明质酸处理可导致腹膜巨噬细胞A20信使核糖核酸（mRNA）表达增加，而在Cd44(-/-)小鼠和Toll样受体4基因敲除（Tlr4(-/-)）小鼠的巨噬细胞中，这种增加显著减少。用小干扰RNA（siRNA）抑制A20反应可抑制透明质酸对LPS细胞因子反应的保护能力。因此，我们的结果表明，透明质酸通过TLR4、CD44和A20发挥作用，刺激一种独特的细胞反应，从而对LPS的脓毒症反应起到保护作用。
