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

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

doi:10.1111/bph.15156

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

13 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 language	English
Pages (from-to)	4055-4073
Number of pages	19
Journal	British Journal of Pharmacology
Volume	177
Issue number	17
DOIs	https://doi.org/10.1111/bph.15156
State	Published - 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

Keywords

CD59 antigen
Protectin D1
Tumor necrosis factor
unclassified drug

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10.1111/bph.15156

Cite this

@article{c61844403a8f407ab7e6576049827faf,

title = "Pro-resolving mediator protectin D1 promotes epimorphic regeneration by controlling immune cell function in vertebrates.",

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.",

keywords = "CD59 antigen, Protectin D1, Tumor necrosis factor, unclassified drug",

author = "Mai Nguyen-Chi and Patricia Luz-Crawford and Laurence Balas and Tamara Sipka and Rafael Contreras-L{\'o}pez and Audrey Barthelaix and Georges Lutfalla and Thierry Durand and Christian Jorgensen and Farida Djouad",

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: {\textcopyright} 2020 The British Pharmacological Society",

year = "2020",

month = sep,

day = "1",

doi = "10.1111/bph.15156",

language = "English",

volume = "177",

pages = "4055--4073",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley-Blackwell",

number = "17",

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TY - JOUR

T1 - Pro-resolving mediator protectin D1 promotes epimorphic regeneration by controlling immune cell function in vertebrates.

AU - Nguyen-Chi, Mai

AU - Luz-Crawford, Patricia

AU - Balas, Laurence

AU - Sipka, Tamara

AU - Contreras-López, Rafael

AU - Barthelaix, Audrey

AU - Lutfalla, Georges

AU - Durand, Thierry

AU - Jorgensen, Christian

AU - Djouad, Farida

N1 - 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

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

KW - CD59 antigen

KW - Protectin D1

KW - Tumor necrosis factor

KW - unclassified drug

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U2 - 10.1111/bph.15156

DO - 10.1111/bph.15156

M3 - Article

C2 - 32520398

AN - SCOPUS:85087555614

SN - 0007-1188

VL - 177

SP - 4055

EP - 4073

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 17

ER -

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

Abstract

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Keywords

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