Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation
Arachidonic acid inhibits inflammatory responses by binding to myeloid differentiation factor-2 (MD2) and preventing MD2/toll-like receptor 4 signaling activation
复制标题
花生四烯酸通过与骨髓分化因子 2 (MD2) 结合并防止 MD2/toll 样受体 4 信号传导激活来抑制炎症反应
DOI：
10.1016/j.bbadis.2020.165683
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发表时间：
2020
影响因子：
6.2
通讯作者：
Guang Liang
中科院分区：
文献类型：
--
作者：
Yali Zhang;Hongjin Chen;Wenxin Zhang;Yan Cai;Peiren Shan;Di Wu;Bing Zhang;Hui Liu;Zia A. Khan;Guang Liang
花生四烯酸（AA）在所有细胞的功能中发挥着重要作用。AA的代谢促进炎症以及用于解决炎症。虽然AA衍生的代谢产物表现出充分证实的生物活性，但尚不清楚AA是否独立于其代谢产物调节炎症反应。最近发现饱和脂肪酸激活Toll样受体4（TLR 4），我们验证了AA通过调节TLR 4的活性直接调节炎症反应的假设。在培养的心肌细胞和巨噬细胞中，我们发现AA阻止饱和脂肪酸诱导的TLR 4复合物与辅助蛋白的形成和促炎细胞因子的诱导。我们发现AA直接与TLR 4辅助受体髓样分化因子2（MD 2）结合，并阻止饱和脂肪酸激活TLR 4促炎信号通路。类似地，AA通过与MD 2结合减少巨噬细胞中脂多糖（LPS）诱导的炎症和小鼠中的脓毒性死亡。在肥胖的高脂饮食小鼠模型和LPS诱导的急性肺损伤模型中，两者都通过TLR 4介导炎症反应，AA治疗阻止了MD 2/TLR 4二聚化、炎症因子的诱导和组织损伤。总之，我们已经发现AA与MD 2相互作用并破坏LPS和饱和脂肪酸对TLR 4的激活。这些发现为AA诱导的炎症调节的直接机制提供了实验证据。
Arachidonic acid (AA) plays a fundamental role in the function of all cells. Metabolites of AA contribute to inflammation as well as for resolving inflammation. Although AA-derived metabolites exhibit well-substantiated bioactivity, it is not known whether AA regulates inflammatory responses independent of its metabolites. With the recent discovery that saturated fatty acids activate toll-like receptor-4 (TLR4), we tested the hypothesis that AA directly regulates inflammatory responses through modulating the activity of TLR4. In cultured cardiomyocytes and macrophages, we found that AA prevents saturated fatty acid-induced TLR4 complex formation with accessory proteins and the induction of proinflammatory cytokines. We discovered that AA directly binds to TLR4 co-receptor, myeloid differentiation factor 2 (MD2) and prevents saturated fatty acids from activating TLR4 pro-inflammatory signaling pathway. Similarly, AA reduced lipopolysaccharide (LPS)-induced inflammation in macrophages and septic death in mice through binding to MD2. In high-fat diet mouse model of obesity and LPS-induced model of acute lung injury, both mediating inflammatory responses through TLR4, treatment with AA prevented MD2/TLR4 dimerization, induction of inflammatory factors, and tissue injuries. In summary, we have discovered that AA interacts with MD2 and disrupts TLR4 activation by LPS and saturated fatty acids. These findings provide experimental evidence for a direct mechanism of AA-induced regulation of inflammation.