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Cell Chem Biol. 2018 Jun 21;25(6):749-760.e9. doi: 10.1016/j.chembiol.2018.04.017. Epub 2018 May 24.

PDn-3 DPA Pathway Regulates Human Monocyte Differentiation and Macrophage Function.

Author information

1
William Harvey Research Institute and John Vane Science Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
2
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068 Blindern, Oslo 0316, Norway.
3
William Harvey Research Institute and John Vane Science Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: j.dalli@qmul.ac.uk.

Abstract

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 (PDn-3 DPA) 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 PDn-3 DPA 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-ePDn-3 DPA). This intermediate was enzymatically converted by epoxide hydrolases to PD1n-3 DPA and PD2n-3 DPA, with epoxide hydrolase 2 converting 16S,17S-ePDn-3 DPA to PD2n-3 DPA in human monocytes. Taken together these results establish the PDn-3 DPA biosynthetic pathway in human monocytes and macrophages and its role in regulating macrophage resolution responses.

KEYWORDS:

lipid mediators; omega-3; resolution; total organic synthesis

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