ABSTRACT
A successful acute inflammatory response results in the elimination of infectious agents by neutrophils and monocytes, followed by resolution and repair by tissue-resident and recruited macrophages. D-series resolvins are pro-resolving mediators involved in resolution and tissue repair, their intracellular signaling mechanism(s) are of interest. Here, we report that D-series resolvins activate phospholipase D (PLD), a ubiquitously expressed membrane lipase in modulating phagocyte functions. The mechanism for PLD-mediated actions of RvD5 in polarizing macrophages (M1-M2) was found to be two-pronged: (a) RvD5 inhibits post-transcriptional modifications, by miRs and 3’exonulceases that process PLD2 mRNA, thus increasing PLD2 expression and activity; (b) RvD5 enhances PLD2-S6K signaling and Actin expression required for membrane expansion and efferocytosis. In addition, investigating RvD5’s actions in second organ reflow injury, we found that RvD5 did not reduce lung neutrophil myeloperoxidase levels in PLD2-/- mice compared to WT and PLD1-/- mice, pointing to a unique role of PLD2 as the relevant isoform in RvD5-mediated resolution. These results demonstrate that RvD5-PLD2 are attractive targets for therapeutic interventions in vascular inflammation such as I/R injury and cardiovascular diseases.
ABBREVIATIONS
- Arg1
- Arginase I
- CD
- Cluster of differentiation
- DHA
- Docosahexanoic acid
- EPA
- Eicosapentanoic acid
- GPR32
- G-protein coupled receptor 32
- HLIR
- Hind-limb ischemia reperfusion
- IFNγ
- Interferon gamma
- IL-12
- Interleukin 12
- IL-4
- Interleukin 4
- iNOS2
- Inducible Nitric oxide synthase 2
- LPS
- Lipopolysaccharide (Bacterial)
- miR
- micro RNA
- MPO
- Myeloperoxidase
- PA
- Phosphatidic acid
- PARN
- Poly(A)-tail ribonuclease
- PBDM
- Peripheral blood-derived macrophages
- PC
- Phosphatidyl choline
- PLD
- Phopsholipase D
- PLD1-/-
- Phospholipase D1 knockout
- PLD2-/-
- Phospholipase D2 knockout
- PMN
- Polymorphonuclear neutrophils
- PPARγ
- Peroxisome-proliferation antagonist receptor gamma
- ROS
- Reactive oxygen species
- RvD1
- 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid/ Resolvin D1
- RvD2
- 7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid/ Resolvin D2
- RvD3
- 4S,11R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-docosahexaenoic acid/ Resolvin D3
- RvD4
- 4S,5,17S-trihydroxy-6E,8E,10E,13E,15Z,19Z-docosahexaenoic acid/ Resolvin D4
- RvD5
- 7S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid/ Resolvin D5
- S6
- Ribosomal protein S6
- phospho S6
- Phosphorylated ribosomal protein S6
- S6K
- p70-S6 Kinase
- SPMs
- Specialized pro-resolving lipid mediators
- TGF-β
- Transforming growth factor beta
- TNFα
- Tumor necrosis factor alpha
- WT
- Wild-type