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

Kimberly Pistorius; Patricia R Souza; Roberta De Matteis; Shani Austin-Williams; Karoline G Primdahl; Anders Vik; Francesca Mazzacuva; Romain A Colas; Raquel M Marques; Trond V Hansen; Jesmond Dalli

doi:10.1016/j.chembiol.2018.04.017

PD_{n-3 DPA} Pathway Regulates Human Monocyte Differentiation and Macrophage Function

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

Affiliations

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: [email protected].

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 (PD_{n-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 PD_{n-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-ePD_{n-3 DPA}). This intermediate was enzymatically converted by epoxide hydrolases to PD1_{n-3 DPA} and PD2_{n-3 DPA}, with epoxide hydrolase 2 converting 16S,17S-ePD_{n-3 DPA} to PD2_{n-3 DPA} in human monocytes. Taken together these results establish the PD_{n-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CD59 Antigens
Fatty Acids, Unsaturated
Lipoxygenase Inhibitors
Arachidonate 15-Lipoxygenase
docosapentaenoic acid