TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection.
TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection.
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TLR4拮抗剂FP7抑制LPS诱导的树突状细胞中的细胞因子产生和糖酵解重编程，并保护小鼠免受致命的流感感染。
DOI：
10.1038/srep40791
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发表时间：
2017-01-20
影响因子：
4.6
通讯作者：
Lotteau V
中科院分区：
文献类型：
--
作者：
Perrin-Cocon L;Aublin-Gex A;Sestito SE;Shirey KA;Patel MC;André P;Blanco JC;Vogel SN;Peri F;Lotteau V
toll样受体(TLR)-4激活失调与急性全身性败血症、慢性炎症性疾病（如动脉粥样硬化和糖尿病）以及病毒感染（如流感感染）有关。因此，TLR4信号通路的治疗性控制具有重要意义。在这里，我们测试了小分子合成TLR4拮抗剂FP7在体外对人单核细胞和单核细胞衍生的树突状细胞（dc）的活性，以及在小鼠流感病毒感染期间的体内活性。我们的研究结果表明，FP7可以拮抗单核细胞和DC （IC50 < 1 μM）分泌促炎细胞因子（IL-6、IL-8和MIP-1β），并在TLR4被超纯脂多糖（LPS）激活时阻止DC成熟。FP7选择性阻断TLR4的刺激，但不阻断TLR1/2、TLR2/6或TLR3的激活。TLR4刺激人dc导致糖酵解活性增加，同时也被FP7拮抗。FP7保护小鼠免受流感病毒诱导的死亡，并降低肺部促炎细胞因子基因表达和急性肺损伤（ALI）。因此，FP7可以在体外拮抗TLR4激活并保护小鼠免受严重流感感染，最可能的是通过减少TLR4依赖性细胞因子风暴介导的损伤相关分子模式（DAMPs），如HMGB1。
Dysregulated Toll-like receptor (TLR)-4 activation is involved in acute systemic sepsis, chronic inflammatory diseases, such as atherosclerosis and diabetes, and in viral infections, such as influenza infection. Thus, therapeutic control of the TLR4 signalling pathway is of major interest. Here we tested the activity of the small-molecule synthetic TLR4 antagonist, FP7, in vitro on human monocytes and monocyte-derived dendritic cells (DCs) and in vivo during influenza virus infection of mice. Our results indicate that FP7 antagonized the secretion of proinflammatory cytokines (IL-6, IL-8, and MIP-1β) by monocytes and DCs (IC50 < 1 μM) and prevented DC maturation upon TLR4 activation by ultrapure lipopolysaccharide (LPS). FP7 selectively blocked TLR4 stimulation, but not TLR1/2, TLR2/6, or TLR3 activation. TLR4 stimulation of human DCs resulted in increased glycolytic activity that was also antagonized by FP7. FP7 protected mice from influenza virus-induced lethality and reduced both proinflammatory cytokine gene expression in the lungs and acute lung injury (ALI). Therefore, FP7 can antagonize TLR4 activation in vitro and protect mice from severe influenza infection, most likely by reducing TLR4-dependent cytokine storm mediated by damage-associated molecular patterns (DAMPs) like HMGB1.