Robertson, A., Ogryzko, N., Henry, K. et al. (14 more authors) (2016) Identification of benzopyrone as a common structural feature in compounds with anti-inflammatory activity in a zebrafish phenotypic screen. Disease Models and Mechanisms, 9 (6). pp. 621-632. ISSN 1754-8403
Abstract
Neutrophils are essential for host defence and are recruited to sites of inflammation in response to tissue injury or infection. For inflammation to resolve, these cells must be cleared efficiently and in a controlled manner, either by apoptosis or reverse migration. If the inflammatory response is not well regulated, persistent neutrophils may cause damage to host tissues and contribute to the pathogenesis of chronic inflammatory diseases, which respond poorly to current treatments. It is therefore important to develop drug discovery strategies that can identify new therapeutics specifically targeting neutrophils, either by promoting their clearance or by preventing their recruitment. Our recent in vivo chemical genetic screen for accelerators of inflammation resolution identified a subset of compounds sharing a common chemical signature, the bicyclic benzopyrone rings. Here, we further investigate the mechanisms of action of the most active of this chemical series, isopimpinellin, in our zebrafish model of neutrophilic inflammation. We found that this compound targets both the recruitment and resolution phases of the inflammatory response. Neutrophil migration towards a site of injury is reduced by isopimpinellin and this occurs as a result of PI3K inhibition. We also show that isopimpinellin induces neutrophil apoptosis to drive inflammation resolution in vivo using a new zebrafish reporter line detecting in vivo neutrophil caspase-3 activity and allowing quantification of flux through the apoptotic pathway in real-time. Finally, our studies reveal that clinically available ‘cromones' are structurally related to isopimpinellin and have previously undescribed pro-resolution activity in vivo. These findings may have implications for the therapeutic use of benzopyrones in inflammatory disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Zebrafish; inflammation; neutrophil apoptosis; chromone; benzopyrone |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection and Immunity (Sheffield) The University of Sheffield > Faculty of Science (Sheffield) > Department of Chemistry (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL (BBSRC) BB/L000830/1 BRITISH HEART FOUNDATION PG/13/80/30443 MEDICAL RESEARCH COUNCIL MR/M004864/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 02 Jun 2016 13:40 |
Last Modified: | 03 Jun 2024 10:45 |
Status: | Published |
Publisher: | Company of Biologists |
Refereed: | Yes |
Identification Number: | 10.1242/dmm.024935 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:100383 |