Abstract
The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells. Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia. This new resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.
Highlights
The acute inflammatory response is a critical and dynamic immunological process during infection and tissue injury (1)
M2 macrophages play critical roles in the resolution of inflammation by virtue of their capacity to carry out efferocytosis (3, 4), wound repair (3, 29), and production of specialized pro-resolving mediators (SPMs) (5)
In human macrophages and neutrophils, Resolvin E4 (RvE4) biosynthesis is dependent on the substrate availability of eicosapentaenoic acid (EPA) released from both phospholipases (PL) and triglycerides (17)
Summary
The acute inflammatory response is a critical and dynamic immunological process during infection and tissue injury (1). Each SPM limits neutrophil infiltration and increases the clearance of apoptotic cells by macrophages (3, 4) In this context, macrophages play a central function in the resolution phase of inflammation by actively clearing apoptotic cells (4) and biosynthesizing distinct families of LMs that can be either pro-inflammatory or antiinflammatory and pro-resolving depending on the macrophage phenotypes and the specific agonists (5, 6). Macrophages play a central function in the resolution phase of inflammation by actively clearing apoptotic cells (4) and biosynthesizing distinct families of LMs that can be either pro-inflammatory or antiinflammatory and pro-resolving depending on the macrophage phenotypes and the specific agonists (5, 6) An example of this is with human macrophages: high-mobility group box 1 protein (HMGB1) stimulates the production of pro-inflammatory cytokines and leukotrienes, while high-mobility group box 1 protein together with complement component 1q (C1q) switches macrophages to produce SPMs (7)
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