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Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration
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)...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744913/ https://www.ncbi.nlm.nih.gov/pubmed/31451657 http://dx.doi.org/10.1073/pnas.1905221116 |
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author | Hsu, Alan Y. Wang, Decheng Liu, Sheng Lu, Justice Syahirah, Ramizah Bennin, David A. Huttenlocher, Anna Umulis, David M. Wan, Jun Deng, Qing |
author_facet | Hsu, Alan Y. Wang, Decheng Liu, Sheng Lu, Justice Syahirah, Ramizah Bennin, David A. Huttenlocher, Anna Umulis, David M. Wan, Jun Deng, Qing |
author_sort | Hsu, Alan Y. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6744913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-67449132019-09-27 Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration Hsu, Alan Y. Wang, Decheng Liu, Sheng Lu, Justice Syahirah, Ramizah Bennin, David A. Huttenlocher, Anna Umulis, David M. Wan, Jun Deng, Qing Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2019-09-10 2019-08-26 /pmc/articles/PMC6744913/ /pubmed/31451657 http://dx.doi.org/10.1073/pnas.1905221116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | PNAS Plus Hsu, Alan Y. Wang, Decheng Liu, Sheng Lu, Justice Syahirah, Ramizah Bennin, David A. Huttenlocher, Anna Umulis, David M. Wan, Jun Deng, Qing Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration |
title | Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration |
title_full | Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration |
title_fullStr | Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration |
title_full_unstemmed | Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration |
title_short | Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration |
title_sort | phenotypical microrna screen reveals a noncanonical role of cdk2 in regulating neutrophil migration |
topic | PNAS Plus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744913/ https://www.ncbi.nlm.nih.gov/pubmed/31451657 http://dx.doi.org/10.1073/pnas.1905221116 |
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