ZFIN ID: ZDB-PUB-140513-461
A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism
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.
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 Medical Research
  • 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.
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