CD317促进巨噬细胞TLR4信号转导的作用机制研究

The Mechanism of CD317 in Promoting TLR4 Signaling in Macrophage

Toll样受体4(TLR4)是一个重要的模式识别受体,在抗感染天然免疫过程中发挥重要作用。CD317是一个结构独特的Ⅱ型跨膜糖蛋白,兼具病毒束缚和信号调节功能,但目前尚不清楚其对TLR4介导的信号转导是否有调控作用。该研究利用基因敲除鼠来源的原代腹腔巨噬细胞和THP-1诱导的人巨噬细胞为模型,探讨了CD317对TLR4信号转导的作用。结果显示,CD317能够被TLR4激动剂脂多糖诱导表达,并反馈性增强脂多糖介导的NF-κB活化及TNF-α、IL-1β和IL-6等促炎细胞因子的产生。CD317敲除或敲减均能够显著抑制TLR4介导信号活化及细胞因子的产生。进一步利用免疫共沉淀证实CD317能够与TLR4下游的关键蛋白MyD88、TRAF6相结合,提示CD317可能是通过MyD88-TRAF6信号转导,增强TLR4介导的NF-κB活化。该研究不仅加深了对CD317在抗感染天然免疫调控中作用的认识,也为相关疾病的治疗策略开发提供了新的靶点和理论指导。

TLR4 is an important pattern recognition receptor that plays important roles in innate immunity against infections.CD317 is a typeⅡtransmembrane glycoprotein with unique structure that endows it viral tethering and signaling potential.However,it is not clear yet whether CD317 regulates TLR4-mediated signal transduction.Herein,we investigated the role of CD317 on TLR4 signal transduction by using primary peritoneal macrophages derived from CD317 knockout mice and THP-1-derived human macrophages,and found that the expression of CD317 could be induced by TLR4 agonist(Lipopolysaccharide),which,in a feedback loop,further enhanced the TLR4-mediated NF-κB activation and subsequent release of pro-inflammatory cytokines(TNF-α,IL-1βand IL-6,etc.).CD317 knockdown or knockout markedly impaired the TLR4 signal transduction and cytokine production.By using co-immunoprecipitation,we found that CD317 could interact with both MyD88 and TRAF6,suggesting that CD317 probably enhanced the TLR-4-mediated NF-κB activation through MyD88-TRAF6 signal transduction pathway.Conclusively,our study not only extends the understanding on the role of CD317 in innate immune regulation,but also provides new targets and theoretical guidance for the development of effective strategies for related diseases.