PUBLICATION

Genetic and pharmacological inhibition of CDK9 drives neutrophil apoptosis to resolve inflammation in zebrafish in vivo

Authors
Hoodless, L.J., Lucas, C.D., Duffin, R., Denvir, M.A., Haslett, C., Tucker, C.S., Rossi, A.G.
ID
ZDB-PUB-161113-16
Date
2016
Source
Scientific Reports   5: 36980 (Journal)
Registered Authors
Duffin, Rodger, Hoodless, Laura, Lucas, Chris, Rossi, Adriano
Keywords
Acute inflammation, Imaging the immune system, Immune cell death
MeSH Terms
  • Animals
  • Apoptosis/drug effects
  • CRISPR-Cas Systems
  • Cyclin-Dependent Kinase 9/genetics*
  • Cyclin-Dependent Kinase 9/metabolism*
  • Disease Models, Animal
  • Flavonoids/pharmacology
  • Gene Knockdown Techniques/methods*
  • Inflammation/immunology*
  • Inflammation/metabolism
  • Macrophages/cytology
  • Macrophages/drug effects
  • Macrophages/metabolism
  • Neutrophils/cytology*
  • Neutrophils/drug effects
  • Neutrophils/metabolism
  • Piperidines/pharmacology
  • Protein Kinase Inhibitors/pharmacology*
  • Pyrazoles/pharmacology
  • Ribonucleoproteins/genetics
  • Ribonucleoproteins/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism*
PubMed
27833165 Full text @ Sci. Rep.
Abstract
Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation. Using live cell imaging in zebrafish with labelled neutrophils and macrophages, we show that pharmacological inhibition, morpholino-mediated knockdown and CRISPR/cas9-mediated knockout of CDK9 enhances inflammation resolution by reducing neutrophil numbers via induction of apoptosis after tailfin injury. Importantly, knockdown of the negative regulator La-related protein 7 (LaRP7) increased neutrophilic inflammation. Our data show that CDK9 is a possible target for controlling resolution of inflammation.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping