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Resolvin E1 and protectin D1 activate inflammation-resolution programmes

Abstract

Resolution of acute inflammation is an active process essential for appropriate host responses, tissue protection and the return to homeostasis1,2,3. During resolution, specific omega-3 polyunsaturated fatty-acid-derived mediators are generated within resolving exudates, including resolvin E1 (RvE1)4 and protectin D1 (PD1)5. It is thus important to pinpoint specific actions of RvE1 and PD1 in regulating tissue resolution. Here we report that RvE1 and PD1 in nanogram quantities promote phagocyte removal during acute inflammation by regulating leukocyte infiltration, increasing macrophage ingestion of apoptotic polymorphonuclear neutrophils in vivo and in vitro, and enhancing the appearance of phagocytes carrying engulfed zymosan in lymph nodes and spleen. In this tissue terrain, inhibition of either cyclooxygenase or lipoxygenases—pivotal enzymes in the temporal generation of both pro-inflammatory and pro-resolving mediators—caused a ‘resolution deficit’ that was rescued by RvE1, PD1 or aspirin-triggered lipoxin A4 analogue. Also, new resolution routes were identified that involve phagocytes traversing perinodal adipose tissues and non-apoptotic polymorphonuclear neutrophils carrying engulfed zymosan to lymph nodes. Together, these results identify new active components for postexudate resolution traffic, and demonstrate that RvE1 and PD1 are potent agonists for resolution of inflamed tissues.

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Figure 1: Pro-resolving lipid mediators RvE1, PD1 and ATLa direct local phagocyte tissue flux.
Figure 2: RvE1 and PD1 increase macrophage phagocytic activity in vivo and in vitro.
Figure 3: RvE1 and PD1 enhance leukocytes carrying phagocytosed zymosan in lymph nodes and spleen.
Figure 4: Active removal of leukocytes from the inflammatory exudate.

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Acknowledgements

These studies were supported in part by the NIH (C.N.S.) and a Research Fellowship from the Deutsche Forschungsgemeinschaft (J.M.S.). We thank J. Kutok for discussion regarding immunohistology, G. Fredman for assistance with fluorescence-activated cell sorting (FACS) and S. Elangovan for technical support. We also thank L. Xu and K. Gotlinger for mass spectral analyses and M. Halm Small for manuscript preparation. We also acknowledge NIH support for the Organic Synthesis Core (NAP) of the NIH-supported P50 Center grant (C.N.S.).

Author Contributions C.N.S. planned the project, designed experiments, analysed data and wrote the manuscript; N.C. and J.M.S. designed and carried out experiments, analysed data, and wrote the manuscript; M.A. analysed and discussed data.

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Correspondence to Charles N. Serhan.

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The Brigham and Women’s Hospital is assigned patents on lipoxins and resolvins that are subjects of licensing agreements and consultant arrangements for C.N.S.

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Schwab, J., Chiang, N., Arita, M. et al. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007). https://doi.org/10.1038/nature05877

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