25-Hydroxycholesterol acts as an amplifier of inflammatory signaling
25-Hydroxycholesterol acts as an amplifier of inflammatory signaling
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DOI：
10.1073/pnas.1404271111
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发表时间：
2014-07-22
影响因子：
11.1
通讯作者：
Aderem, Alan
中科院分区：
文献类型：
--
作者：
Gold, Elizabeth S.;Diercks, Alan H.;Aderem, Alan
类固醇调节通路和炎症通路之间的相互作用已被证明显著影响动脉粥样硬化和感染性疾病的发展。氧化甾醇25-羟基胆固醇(25HC)在脂质生物合成和免疫中起着多种作用。我们最近使用系统生物学的方法来确定25HC是一种先天免疫介质，在动脉粥样硬化中具有预测作用，我们还证明了25HC在泡沫细胞形成中的作用。在这里，我们展示了这个介体在抗病毒反应中也有几个复杂的角色。宿主对病毒的反应涉及具有多个反馈回路的基因调节电路，我们在这里展示了25HC在巨噬细胞中作为炎症信号的放大器。我们确定，25HC至少部分地通过介导AP-1组分FBJ骨肉瘤癌基因(FOS)和JUN原癌基因(JUN)招募到Toll样受体反应基因子集的启动子来放大炎症信号。与以前的报道一致，我们发现25HC在体外抑制流感对呼吸道上皮细胞的感染。令人惊讶的是，我们发现CH25H的缺失对流感感染的小鼠模型具有保护作用，因为炎症诱导的病理减少了。CH25H是编码产生25HC的酶的基因。因此，我们的研究首次证明，据我们所知，除了直接的抗病毒作用外，25HC还通过AP-1调节转录反应并作为炎症的放大器，由此导致的炎症反应的改变导致感染流感后小鼠组织损伤的增加。
Cross-talk between sterol regulatory pathways and inflammatory pathways has been demonstrated to significantly impact the development of both atherosclerosis and infectious disease. The oxysterol 25-hydroxycholesterol (25HC) plays multiple roles in lipid biosynthesis and immunity. We recently used a systems biology approach to identify 25HC as an innate immune mediator that had a predicted role in atherosclerosis and we demonstrated a role for 25HC in foam cell formation. Here, we show that this mediator also has several complex roles in the antiviral response. The host response to viruses involves gene regulatory circuits with multiple feedback loops and we show here that 25HC acts as an amplifier of inflammatory signaling in macrophages. We determined that 25HC amplifies inflammatory signaling, at least in part, by mediating the recruitment of the AP-1 components FBJ osteosarcoma oncogene (FOS) and jun proto-oncogene (JUN) to the promoters of a subset of Toll-like receptor-responsive genes. Consistent with previous reports, we found that 25HC inhibits in vitro infection of airway epithelial cells by influenza. Surprisingly, we found that deletion of Ch25h, the gene encoding the enzyme responsible for 25HC production, is protective in a mouse model of influenza infection as a result of decreased inflammatory-induced pathology. Thus, our study demonstrates, for the first time to our knowledge, that in addition to its direct antiviral role, 25HC also regulates transcriptional responses and acts as an amplifier of inflammation via AP-1 and that the resulting alteration in inflammatory response leads to increased tissue damage in mice following infection with influenza.