Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo.
Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo.
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DOI：
10.1038/srep36980
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发表时间：
2016-11-11
影响因子：
4.6
通讯作者：
Rossi AG
中科院分区：
文献类型：
--
作者：
Hoodless LJ;Lucas CD;Duffin R;Denvir MA;Haslett C;Tucker CS;Rossi AG
中性粒细胞炎症受到严格调节，随后消退以限制组织损伤并促进修复。当炎症的及时解决失调时，组织损伤和疾病就会发生。一个关键的控制机制是中性粒细胞凋亡，随后是吞噬细胞如巨噬细胞清除凋亡细胞。细胞周期蛋白依赖性激酶（CDK）抑制剂药物在体外诱导中性粒细胞凋亡并促进啮齿动物模型炎症的消退。在这里，我们提出了第一个体内证据，使用药理学和遗传学方法，CDK9参与中性粒细胞依赖性炎症的解决。利用斑马鱼的活细胞成像技术，研究人员发现，在尾鳍损伤后，药物抑制、morpholino介导的敲除和CRISPR/cas9介导的敲除CDK9，通过诱导细胞凋亡来减少中性粒细胞数量，从而增强炎症的缓解。重要的是，负调节因子la相关蛋白7 （LaRP7）的敲低会增加中性粒细胞炎症。我们的数据表明，CDK9是控制炎症消退的可能靶标。
Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholino-mediated knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation.
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影响因子：
9.2
作者：
Feng, Yi;Renshaw, Stephen;Martin, Paul
通讯作者：
Martin, Paul
DOI：
10.1007/978-1-4939-2926-9_15
发表时间：
2016-01-01
期刊：
CYCLIN-DEPENDENT KINASE (CDK) INHIBITORS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Hoodless, Laura J.;Robb, Calum T.;Rossi, Adriano G.
通讯作者：
Rossi, Adriano G.
影响因子：
5.5
作者：
Brown, Simon B.;Tucker, Carl S.;Mullins, John J.
通讯作者：
Mullins, John J.
影响因子：
3.7
作者：
Alessandri AL;Duffin R;Leitch AE;Lucas CD;Sheldrake TA;Dorward DA;Hirani N;Pinho V;de Sousa LP;Teixeira MM;Lyons JF;Haslett C;Rossi AG
通讯作者：
Rossi AG
影响因子：
5.5
作者：
Loynes, Catherine A.;Martin, Jane S.;Renshaw, Stephen A.
通讯作者：
Renshaw, Stephen A.