RT Journal Article
SR Electronic
T1 Resolvin D-series regulates Phospholipase D both during inflammation and resolution by modulating phagocyte functions
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 827295
DO 10.1101/827295
A1 Ramya Ganesan
A1 Karen M. Henkels
A1 Krushangi Shah
A1 Xavier de la Rosa
A1 Stephania Libreros
A1 Nagarjuna R Cheemarla
A1 Charles N. Serhan
A1 Julian Gomez-Cambronero
YR 2019
UL http://biorxiv.org/content/early/2019/11/02/827295.abstract
AB 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.Arg1Arginase ICDCluster of differentiationDHADocosahexanoic acidEPAEicosapentanoic acidGPR32G-protein coupled receptor 32HLIRHind-limb ischemia reperfusionIFNγInterferon gammaIL-12Interleukin 12IL-4Interleukin 4iNOS2Inducible Nitric oxide synthase 2LPSLipopolysaccharide (Bacterial)miRmicro RNAMPOMyeloperoxidasePAPhosphatidic acidPARNPoly(A)-tail ribonucleasePBDMPeripheral blood-derived macrophagesPCPhosphatidyl cholinePLDPhopsholipase DPLD1-/-Phospholipase D1 knockoutPLD2-/-Phospholipase D2 knockoutPMNPolymorphonuclear neutrophilsPPARγPeroxisome-proliferation antagonist receptor gammaROSReactive oxygen speciesRvD17S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid/ Resolvin D1RvD27S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-docosahexaenoic acid/ Resolvin D2RvD34S,11R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-docosahexaenoic acid/ Resolvin D3RvD44S,5,17S-trihydroxy-6E,8E,10E,13E,15Z,19Z-docosahexaenoic acid/ Resolvin D4RvD57S,17S-dihydroxy-4Z,8E,10Z,13Z,15E,19Z-docosahexaenoic acid/ Resolvin D5S6Ribosomal protein S6phospho S6Phosphorylated ribosomal protein S6S6Kp70-S6 KinaseSPMsSpecialized pro-resolving lipid mediatorsTGF-βTransforming growth factor betaTNFαTumor necrosis factor alphaWTWild-type