Pro-resolving mediator protectin D1 promotes epimorphic regeneration by controlling immune cell function in vertebrates

Mai Nguyen-Chi, Patricia Alejandra Luz Crawford, Laurence Balas, Tamara Sipka, Rafael Contreras-López, Audrey Barthelaix, Georges Lutfalla, Thierry Durand, Christian Jorgensen, Farida Djouad

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background and Purpose: Specialized pro-resolving mediators (SPMs) are a family of lipids controlling the resolution of inflammation and playing a role in many processes including organ protection and tissue repair. While SPMs are potent bioactive molecules in vivo, their role in epimorphic regeneration of organs in vertebrates has not been tested. Using the zebrafish larva as a robust regenerative vertebrate system, we studied the role of the SPM neuroprotectin/protectin D1 (PD1) during the caudal fin fold regeneration. Experimental Approach: Regeneration of the fin fold was analysed when exposed to a synthetic PD1. The effect of PD1 on immune cell recruitment and activation was further investigated using live imaging combined with fluorescent reporter lines. Using genetic and pharmacological approaches, we dissected the role of neutrophils and macrophages on driving the pro-regenerative effect of PD1. Key Results: We showed that PD1 improves fin fold regeneration. Acting in a narrow time window during regeneration, PD1 accelerates the resolution of inflammation without affecting the initial kinetic of neutrophil recruitment but instead, promotes their reverse migration potential. In addition, PD1 induces macrophage polarization switch towards non-inflammatory states in both zebrafish and mammalian system. Finally, macrophages but not neutrophils are essential for PD1-mediated regeneration. Conclusion and Implications: These results reveal the pro-regenerative action of PD1 and its role in regulating neutrophil and macrophage response in vertebrates. These findings strongly support the development of pro-resolving mediators as natural therapeutic candidates for degenerative disorders and the use of the zebrafish as a tool to investigate pro-regenerative drugs.

Original languageEnglish
Pages (from-to)4055-4073
Number of pages19
JournalBritish Journal of Pharmacology
Volume177
Issue number17
DOIs
StatePublished - 1 Sep 2020

Bibliographical note

Funding Information:
We thank the imaging facility MRI, member of the national infrastructure France‐BioImaging infrastructure supported by the French National Research Agency (ANR‐10‐INBS‐04, “Investments for the future”), Laure Yatime for the analysis of GPR37 orthologues in the zebrafish, J‐P. Levraud (Institut Pasteur, France) for trans‐shipping the line, line and and M. Bagnat for line. We also thank Catherine Gonzalez and Stephane Castel for taking care of the Zebrafish facility of the University of Montpellier. We thank Victor Mulero for sending the recombinant zfTnfa. This work was supported by INSERM, a grant from the European Community's H2020 Program (Marie‐Curie Innovative Training Network ImageInLife: Grant Agreement no. 721537). Funding sources had no role in the writing of the manuscript or the decision to submit it for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Tg(mpx:Dendra2)uwm4 Tg(mpeg1:Gal4/UAS:nfsB‐mCherry) Tg(mpx:Gal4/UAS:nfsB‐mCherry) Tg(rcn3:gal4/UAS:mCherry)

Funding Information:
We thank the imaging facility MRI, member of the national infrastructure France-BioImaging infrastructure supported by the French National Research Agency (ANR-10-INBS-04, ?Investments for the future?), Laure Yatime for the analysis of GPR37 orthologues in the zebrafish, J-P. Levraud (Institut Pasteur, France) for trans-shipping the Tg(mpx:Dendra2)uwm4 line, Tg(mpeg1:Gal4/UAS:nfsB-mCherry) line and Tg(mpx:Gal4/UAS:nfsB-mCherry) and M. Bagnat for Tg(rcn3:gal4/UAS:mCherry) line. We also thank Catherine Gonzalez and Stephane Castel for taking care of the Zebrafish facility of the University of Montpellier. We thank Victor Mulero for sending the recombinant zfTnfa. This work was supported by INSERM, a grant from the European Community's H2020 Program (Marie-Curie Innovative Training Network ImageInLife: Grant Agreement no. 721537). Funding sources had no role in the writing of the manuscript or the decision to submit it for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Publisher Copyright:
© 2020 The British Pharmacological Society

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