PUBLICATION

A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism

Authors
Robertson, A.L., Holmes, G.R., Bojarczuk, A.N., Burgon, J., Loynes, C.A., Chimen, M., Sawtell, A.K., Hamza, B., Willson, J., Walmsley, S.R., Anderson, S.R., Coles, M.C., Farrow, S.N., Solari, R., Jones, S., Prince, L.R., Irimia, D., Rainger, G.E., Kadirkamanathan, V., Whyte, M.K., Renshaw, S.A.
ID
ZDB-PUB-140513-461
Date
2014
Source
Science Translational Medicine   6: 225ra29 (Journal)
Registered Authors
Bojarczuk, Aleks, Burgon, Joseph, Loynes, Catherine, Renshaw, Steve A., Robertson, Anne
Keywords
none
MeSH Terms
  • Abietanes/pharmacology*
  • Animals
  • Animals, Genetically Modified
  • Anti-Inflammatory Agents/pharmacology*
  • Apoptosis/drug effects
  • Cell Movement/drug effects*
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Green Fluorescent Proteins/biosynthesis
  • Green Fluorescent Proteins/genetics
  • High-Throughput Screening Assays*
  • Humans
  • Inflammation/drug therapy*
  • Inflammation/genetics
  • Inflammation/immunology
  • Inflammation/metabolism
  • Inflammation/pathology
  • Larva
  • Neutrophil Infiltration/drug effects*
  • Neutrophils/drug effects*
  • Neutrophils/immunology
  • Neutrophils/metabolism
  • Neutrophils/pathology
  • Signal Transduction/drug effects
  • Time Factors
  • Translational Research, Biomedical
  • Zebrafish*/embryology
  • Zebrafish*/genetics
  • Zebrafish*/immunology
  • Zebrafish*/metabolism
PubMed
24574340 Full text @ Sci. Transl. Med.
Abstract
Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes