title: A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism.
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.
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Robertson
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Holmes
authors.forename: Aleksandra N
authors.initials: AN
authors.lastname: Bojarczuk
authors.forename: Joseph
authors.initials: J
authors.lastname: Burgon
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Loynes
authors.forename: Myriam
authors.initials: M
authors.lastname: Chimen
authors.forename: Amy K
authors.initials: AK
authors.lastname: Sawtell
authors.forename: Bashar
authors.initials: B
authors.lastname: Hamza
authors.forename: Joseph
authors.initials: J
authors.lastname: Willson
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Walmsley
authors.forename: Sean R
authors.initials: SR
authors.lastname: Anderson
authors.forename: Mark C
authors.initials: MC
authors.lastname: Coles
authors.forename: Stuart N
authors.initials: SN
authors.lastname: Farrow
authors.forename: Roberto
authors.initials: R
authors.lastname: Solari
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.forename: Lynne R
authors.initials: LR
authors.lastname: Prince
authors.forename: Daniel
authors.initials: D
authors.lastname: Irimia
authors.forename: G Ed
authors.initials: GE
authors.lastname: Rainger
authors.forename: Visakan
authors.initials: V
authors.lastname: Kadirkamanathan
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Renshaw
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007814:Larva; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D057170:Translational Research, Biomedical; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D045784:Abietanes; D000893:Anti-Inflammatory Agents; C021751:tanshinone; D049452:Green Fluorescent Proteins