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Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18561-18570. doi: 10.1073/pnas.1905221116. Epub 2019 Aug 26.

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

Author information

1
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907.
2
The Institute of Infection and Inflammation, Medical College of China Three Gorges University, 443002 Yichang, Hubei, People's Republic of China.
3
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202.
4
Collaborative Core for Cancer Bioinformatics, Indiana University Simon Cancer Center, Indianapolis, IN 46202.
5
Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706.
6
Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706.
7
Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907.
8
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907.
9
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202.
10
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907; qingdeng@purdue.edu.
11
Purdue Institute for Inflammation, Immunology, & Infectious Disease, Purdue University, West Lafayette, IN 47907.
12
Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907.

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.

KEYWORDS:

chemotaxis; cyclin-dependent kinase 2; innate immunity; microRNA; zebrafish

PMID:
31451657
DOI:
10.1073/pnas.1905221116
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