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bioRxiv · 10.1101/205997

Lipid mediator class-switching downstream of PGE2 determines the outcome of inflammation resolution in vivo.

Loynes, C. A.·Lee, J. A.·Robertson, A. L.·Steel, M. J. G.·Ellett, F.·Feng, Y.·Levy, B. D.·Whyte, M. K.·Renshaw, S. A.
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Abstract

Neutrophils are the first immune cells recruited to a site of injury or infection, where they perform many functions. Having completed their role, neutrophils must be removed from the inflammatory site - either by apoptosis and efferocytosis or by reverse migration away from the wound - for restoration of normal tissue homeostasis. Disruption of these tightly controlled physiological processes of neutrophil removal can lead to a range of inflammatory diseases. We used an in vivo zebrafish model to understand the role of lipid mediator production in neutrophil removal. Following tailfin amputation in the absence of macrophages, neutrophillic inflammation does not resolve. This is due to loss of macrophage-dependent production of eicosanoid prostaglandin E2, which drives neutrophil removal via promotion of reverse migration. Knockdown of endogenous prostaglandin E synthase gene reveals PGE2 as essential for neutrophil inflammation resolution. Furthermore, PGE2 is able to signal through EP4 receptors to enhance Alox15 production, causing a switch towards anti-inflammatory eicosanoid signalling, specifically Lipoxin A4. Our data confirm regulation of neutrophil migration by PGE2 and LXA4 in an in vivo model of inflammation resolution. This pathway may contain therapeutic targets for driving inflammation resolution in chronic inflammatory disease.

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Loynes, C. A., Lee, J. A., Robertson, A. L., Steel, M. J. G., Ellett, F., Feng, Y., Levy, B. D., Whyte, M. K., Renshaw, S. A.. 2017-10-19. Lipid mediator class-switching downstream of PGE2 determines the outcome of inflammation resolution in vivo.. https://doi.org/10.1101/205997

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