Abstract
ABSTRACTNeutrophils 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 can 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 could have implications for the therapeutic use of benzopyrones in inflammatory disease.
Highlights
The acute inflammatory response is an essential host defence mechanism and is initiated by the innate immune system in the event of tissue injury or infection
Larvae were treated with compounds once inflammation was already established at 6 hours post-injury and their effects on neutrophil number were assessed at 12 hpi
We found that when zebrafish larvae were exposed to isopimpinellin once inflammation was already established at 6 hpi, there was a concentration-dependent reduction in neutrophil numbers at the wound at 12 hpi (Fig. 3A)
Summary
The acute inflammatory response is an essential host defence mechanism and is initiated by the innate immune system in the event of tissue injury or infection. It is a highly controlled sequence of events that involves the coordinated activity of multiple cytokines, lipid mediators and cell types, and can be broadly split into three phases: recruitment, peak inflammation and resolution (Serhan et al, 2007). These cells are activated in response to inflammatory stimuli and migrate to inflamed tissue, following gradients of soluble chemokines such as interleukin-8 (IL-8 or CXCL8) (Medzhitov, 2008). Neutrophils are removed either by undergoing apoptosis and engulfment by macrophages, or by leaving the site of inflammation by reverse migration (Henry et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
