Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

被引:40
作者
Hsu, Alan Y. [1 ]
Wang, Decheng [1 ,2 ]
Liu, Sheng [3 ,4 ]
Lu, Justice [1 ]
Syahirah, Ramizah [1 ]
Bennin, David A. [5 ]
Huttenlocher, Anna [5 ,6 ]
Umulis, David M. [7 ,8 ]
Wan, Jun [3 ,4 ,9 ]
Deng, Qing [1 ,10 ,11 ]
机构
[1] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA
[2] China Three Gorges Univ, Coll Med, Inst Infect & Inflammat, Yichang 443002, Hubei, Peoples R China
[3] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA
[4] Indiana Univ, Simon Canc Ctr, Collaborat Core Canc Bioinformat, Indianapolis, IN 46202 USA
[5] Univ Wisconsin Madison, Dept Med Microbiol & Immunol, Madison, WI 53706 USA
[6] Univ Wisconsin Madison, Dept Pediat, Madison, WI 53706 USA
[7] Purdue Univ, Dept Agr & Biol Engn, W Lafayette, IN 47907 USA
[8] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA
[9] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA
[10] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA
[11] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA
关键词
microRNA; cyclin-dependent kinase 2; chemotaxis; zebrafish; innate immunity; CYCLIN-DEPENDENT KINASES; CELL-CYCLE; ZEBRAFISH; CANCER; MECHANISMS; DISEASE; TARGETS; PROLIFERATION; TRANSCRIPTION; THERAPEUTICS;
D O I
10.1073/pnas.1905221116
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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, miR-199 decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils, miR-199 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, miR-199 overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions of miR-199 and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation.
引用
收藏
页码:18561 / 18570
页数:10
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