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.

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.

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