Department of Biological Sciences, Purdue University, West Lafayette, IN 47907.
The Institute of Infection and Inflammation, Medical College of China Three Gorges University, 443002 Yichang, Hubei, People's Republic of China.
Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18561-18570. doi: 10.1073/pnas.1905221116. Epub 2019 Aug 26.
Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those, decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils, alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (Cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore, overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions of and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation.
中性粒细胞迁移对于炎症反应杀死病原体至关重要；然而，过度的中性粒细胞炎症也会导致组织损伤和不良影响。为了发现调节中性粒细胞迁移的新型治疗靶点，我们在斑马鱼中进行了中性粒细胞特异性 microRNA（miRNA）过表达筛选，并鉴定出 8 种 miRNA 作为强烈抑制中性粒细胞迁移的因子。其中， 降低了斑马鱼和人中性粒细胞样细胞的趋化性。有趣的是，在终末分化的中性粒细胞中， 改变了与细胞周期相关的途径，并直接抑制细胞周期蛋白依赖性激酶 2（Cdk2），其已知活性仅限于细胞周期进程和细胞分化。抑制 Cdk2（而非 DNA 复制）会破坏斑马鱼中性粒细胞的细胞极性和趋化性，而不会诱导细胞死亡。缺乏 CDK2 的人中性粒细胞样细胞无法极化，并显示出与甲酰肽受体下游信号的改变。原发性人中性粒细胞的趋化性也会因 CDK2 抑制而降低。此外， 过表达或 CDK2 抑制可显著改善斑马鱼致死性全身炎症挑战的结果。因此，我们的研究结果揭示了 和 CDK2 在调节中性粒细胞迁移中的先前未知功能，并为减轻全身炎症提供了方向。
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