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ZFIN ID: ZDB-PUB-190828-10
Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration
Hsu, A.Y., Wang, D., Liu, S., Lu, J., Syahirah, R., Bennin, D.A., Huttenlocher, A., Umulis, D.M., Wan, J., Deng, Q.
Date: 2019
Source: Proceedings of the National Academy of Sciences of the United States of America   116(37): 18561-18570 (Journal)
Registered Authors: Deng, Qing, Hsu, Alan, Huttenlocher, Anna
Keywords: chemotaxis, cyclin-dependent kinase 2, innate immunity, microRNA, zebrafish
Microarrays: GEO:GSE127174
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Line, Tumor
  • Chemotaxis, Leukocyte/drug effects
  • Chemotaxis, Leukocyte/genetics*
  • Chemotaxis, Leukocyte/immunology
  • Cyclin-Dependent Kinase 2/antagonists & inhibitors
  • Cyclin-Dependent Kinase 2/genetics*
  • Cyclin-Dependent Kinase 2/immunology
  • Disease Models, Animal
  • Down-Regulation/immunology
  • Gene Knockdown Techniques
  • Humans
  • Larva
  • MicroRNAs/metabolism*
  • Neutrophils/immunology*
  • Primary Cell Culture
  • Protein Kinase Inhibitors/pharmacology
  • Signal Transduction/genetics
  • Signal Transduction/immunology
  • Systemic Inflammatory Response Syndrome/genetics
  • Systemic Inflammatory Response Syndrome/immunology*
  • Zebrafish
PubMed: 31451657 Full text @ Proc. Natl. Acad. Sci. USA
FIGURES
ABSTRACT
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.
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