Identification of benzopyrone as a common structural feature in compounds with anti-inflammatory activity in a zebrafish phenotypic screen.
Identification of benzopyrone as a common structural feature in compounds with anti-inflammatory activity in a zebrafish phenotypic screen.
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DOI：
10.1242/dmm.024935
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发表时间：
2016-06-01
影响因子：
4.3
通讯作者：
Renshaw SA
中科院分区：
文献类型：
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作者：
Robertson AL;Ogryzko NV;Henry KM;Loynes CA;Foulkes MJ;Meloni MM;Wang X;Ford C;Jackson M;Ingham PW;Wilson HL;Farrow SN;Solari R;Flower RJ;Jones S;Whyte MK;Renshaw SA
中性粒细胞对于宿主防御是必需的，并且响应于组织损伤或感染而被募集到炎症部位。为了解决炎症，这些细胞必须通过细胞凋亡或反向迁移以有效和受控的方式清除。如果炎症反应没有得到很好的调节，持续的中性粒细胞可能会对宿主组织造成损害，并导致慢性炎症性疾病的发病机制，而慢性炎症性疾病对目前的治疗反应很差。因此，重要的是开发药物发现策略，可以通过促进其清除或防止其招募来识别特异性靶向中性粒细胞的新疗法。我们最近在体内化学遗传筛选炎症解决的加速剂确定了一个子集的化合物共享一个共同的化学签名，双环苯并吡喃酮环。在这里，我们进一步研究了最活跃的化学系列，isopimpinellin，在我们的斑马鱼模型的嗜中性炎症的作用机制。我们发现这种化合物靶向炎症反应的募集和消退阶段。异茴芹素减少了神经元向损伤部位的迁移，这是由于PI 3 K抑制而发生的。我们还表明，isopimpinellin诱导中性粒细胞凋亡，以驱动体内炎症消退，使用新的斑马鱼报告线检测体内中性粒细胞半胱天冬酶-3活性，并允许量化通过凋亡途径的流量在真实的时间。最后，我们的研究表明，临床上可用的“色酮”的结构相关的isopimpinellin和以前未描述的前分辨率在体内的活动。这些发现可能对苯并吡喃酮在炎症性疾病中的治疗用途有影响。总结：斑马鱼炎症筛选鉴定了一系列新的具有抗炎和促消退活性的结构相关化合物，并揭示了临床色酮的一种先前未知的作用机制。
Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or reverse migration. If the inflammatory response is not well-regulated, persistent neutrophils can cause damage to host tissues and contribute to the pathogenesis of chronic inflammatory diseases, which respond poorly to current treatments. It is therefore important to develop drug discovery strategies that can identify new therapeutics specifically targeting neutrophils, either by promoting their clearance or by preventing their recruitment. Our recent in vivo chemical genetic screen for accelerators of inflammation resolution identified a subset of compounds sharing a common chemical signature, the bicyclic benzopyrone rings. Here, we further investigate the mechanisms of action of the most active of this chemical series, isopimpinellin, in our zebrafish model of neutrophilic inflammation. We found that this compound targets both the recruitment and resolution phases of the inflammatory response. Neutrophil migration towards a site of injury is reduced by isopimpinellin and this occurs as a result of PI3K inhibition. We also show that isopimpinellin induces neutrophil apoptosis to drive inflammation resolution in vivo using a new zebrafish reporter line detecting in vivo neutrophil caspase-3 activity and allowing quantification of flux through the apoptotic pathway in real time. Finally, our studies reveal that clinically available ‘cromones’ are structurally related to isopimpinellin and have previously undescribed pro-resolution activity in vivo. These findings could have implications for the therapeutic use of benzopyrones in inflammatory disease. Summary: Zebrafish inflammation screen identifies a new series of structurally related compounds with combined anti-inflammatory and pro-resolution activity, and reveals a previously unknown mechanism of action of clinical cromones.