PD n-3 DPA Pathway Regulates Human Monocyte Differentiation and Macrophage Function

• Published in: Cell chemical biology Vol. 25; no. 6; p. 749
• Main Authors: Pistorius, Kimberly, Souza, Patricia R, De Matteis, Roberta, Austin-Williams, Shani, Primdahl, Karoline G, Vik, Anders, Mazzacuva, Francesca, Colas, Romain A, Marques, Raquel M, Hansen, Trond V, Dalli, Jesmond
• Format: Journal Article
• Language: English
• Published: United States 21-06-2018
• Subjects: Arachidonate 15-Lipoxygenase - metabolism; CD59 Antigens - antagonists & inhibitors; CD59 Antigens - chemistry; CD59 Antigens - metabolism; Cell Differentiation - drug effects; Fatty Acids, Unsaturated - antagonists & inhibitors; Fatty Acids, Unsaturated - chemistry; Fatty Acids, Unsaturated - metabolism; Healthy Volunteers; Humans; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Macrophages - drug effects; Macrophages - physiology; Molecular Structure; Stereoisomerism; lipid mediators; omega-3; total organic synthesis; resolution
• ISSN: 2451-9448

Macrophages are central in orchestrating the clearance of apoptotic cells and cellular debris during inflammation, with the mechanism(s) regulating this process remaining of interest. Herein, we found that the n-3 docosapentaenoic acid-derived protectin (PD
) biosynthetic pathway regulated the differentiation of human monocytes, altering macrophage phenotype, efferocytosis, and bacterial phagocytosis. Using lipid mediator profiling, human primary cells and recombinant enzymes we found that human 15-lipoxygenases initiate the PD
pathway catalyzing the formation of an allylic epoxide. The complete stereochemistry of this epoxide was determined using stereocontrolled total organic synthesis as 16S,17S-epoxy-7Z,10Z,12E,14E,19Z-docosapentaenoic acid (16S,17S-ePD
). This intermediate was enzymatically converted by epoxide hydrolases to PD1
and PD2
, with epoxide hydrolase 2 converting 16S,17S-ePD
to PD2
in human monocytes. Taken together these results establish the PD
biosynthetic pathway in human monocytes and macrophages and its role in regulating macrophage resolution responses.