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

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, whose 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 toward 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.