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Author Notes:

Ramya Ganesan, Department of Medicine, Emory University, School of Medicine, Health Sciences Research Building E269(E2,F2),1760 Haygood Dr, Atlanta, GA 30322, USA. Email: ramya.ganesan@emory.edu

R.G. designed the study, performed experiments and data analysis, prepared figures and wrote the manuscript. J.G.C. conceived and supervised research, contributed to manuscript preparation and critically edited the manuscript. K.M.H. and K.S. carried out experiments and data analysis and contributed to manuscript and figure preparation. C.N.S supervised research and contributed to manuscript preparation and critically edited the manuscript. N.R.C contributed to data analysis and critically edited the manuscript. X.d.l.R. and S.L. performed and analyzed experiments, contributed to manuscript preparation and revision.

We thank Dr. Yasunori Kanaho and Dr. Gilbert Di Paolo for providing us the PLD2 and PLD1 knockout mice, respectively. We thank Dr. Kristen Fite for helpful suggestions and comments on this study. This work is dedicated in loving memory of our dearest colleague, mentor and friend, Prof. Julian Gomez-Cambronero. The experiments reported herein were initiated while Dr. Gomez-Cambronero was on sabbatical in the CNS lab in Boston before his untimely passing.

The authors declare no competing financial interests.

Subjects:

Research Funding:

The following grants to Dr. Cambronero (J.G.C) have supported this work: HL056653-14 from the National Institutes of Health (NIH) and 13GRNT17230097 from the American Heart Association. Experiments in the CNS lab Boston,MA were supported by National Institutes of Health grant P01GM095467 (CNS).

Keywords:

  • Macrophages
  • Inflammation
  • Resolution
  • Phospholipase D
  • Resolvins D-series
  • Polarization

D-series Resolvins activate Phospholipase D in phagocytes during inflammation and resolution

Tools:

Journal Title:

FASEB JOURNAL

Volume:

Volume 34, Number 12

Publisher:

, Pages 15888-15906

Type of Work:

Article | Post-print: After Peer Review

Abstract:

A successful acute inflammatory response results in the elimination of infectious agents by neutrophils and monocytes, followed by resolution and repair through tissue-resident and recruited macrophages. Resolvins (D-series and E-series) are pro-resolving lipid mediators involved in resolution and tissue repair, who’s intracellular signaling remains of interest. Here, we report that D-series resolvins (RvD1- RvD5) activate phospholipase D (PLD), a ubiquitously expressed membrane lipase enzyme activity in modulating phagocyte functions. The mechanism for PLD-mediated actions of Resolvin-D5 (RvD5) in polarizing macrophages (M1-like towards M2-like) was found to be two-pronged: (a) RvD5 inhibits post-transcriptional modifications, by miRs and 3’exonucleases that process PLD2 mRNA, thus increasing PLD2 expression and activity; and (b) RvD5 enhances PLD2-S6Kinase signaling required for membrane expansion and efferocytosis. In an in vivo model of second organ reflow injury, we found that RvD5 did not reduce lung neutrophil myeloperoxidase levels in PLD2−/− mice compared to WT and PLD1−/− mice, confirming a novel role of PLD2 as the isoform in RvD5-mediated resolution processes. These results demonstrate that RvD5-PLD2 are attractive targets for therapeutic interventions in vascular inflammation such as ischemia-reperfusion injury and cardiovascular diseases.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/rdf).
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