PT - JOURNAL ARTICLE AU - Alan Y. Hsu AU - Decheng Wang AU - Sheng Liu AU - Justice Lu AU - Ramizah Syahirah AU - David A. Bennin AU - Anna Huttenlocher AU - Jun Wan AU - Qing Deng TI - MicroRNA Overexpression screen reveals a noncanonical role of CDK2 in regulating neutrophil migration AID - 10.1101/574335 DP - 2019 Jan 01 TA - bioRxiv PG - 574335 4099 - http://biorxiv.org/content/early/2019/03/11/574335.short 4100 - http://biorxiv.org/content/early/2019/03/11/574335.full AB - Neutrophil migration is essential for inflammatory responses to kill pathogens and cause tissue injury. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA overexpression screen in zebrafish, and identified eight microRNAs 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. Chemotaxis of primary human neutrophils are also reduced by CDK2 inhibition. Furthermore, miR-199 overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Together, our results reveal previously unknown functions of miR-199 and CDK2 in regulating neutrophil migration and provide new directions in alleviating systemic inflammation.