Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution

Abstract

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators.

Figure 1. Acute inflammation cellular and chemical mediators

(A) At the onset of acute inflammation, vascular leakage (oedema) occurs. Neutrophils are among the first responders during an acute inflammatory response, followed by monocytes and macrophages. The first cellular hallmark of tissue resolution is a decrease in neutrophil infiltration. Updated from [1]. Classically, eicosanoids such as PGE₂, TXA₂ and LTB₄ (B, red) are known to exert pro-inflammatory actions such as vasodilatation, platelet activation and chemotaxis respectively. Proresolving molecules are generated during inflammation that block vasodilatation/oedema formation and limit further chemotaxis thus allowing for the return to homoeostasis. (B, blue) (B) Scheme of eicosanoid and SPM generation. AA-derived eicosanoids are in red. EPA-derived E-series resolvins, DHA-derived D-series resolvins, protectins and maresins are in blue.

Figure 2. RvE1 has potent and stereoselective action on human platelets

(A) RvE1 (grey) and its stable isomer 19-para-fluorophenoxy-RvE1 (black) both reduced ADP-stimulated platelet aggregation. The biologically inactive isomer of RvE1, Δ6,14-trans isomer (red) did not block ADP-stimulated platelet aggregation. (B) Representative real-time aggregation tracings for Δ6,14-trans isomer (left-hand panel) and 19-para-fluorophenoxy-RvE1 (right-hand panel).

Figure 3. RvE1 has protective actions on human platelets

Aspirin acetylated COX-2 in vascular endothelial cells contributes to the formation of RvE1 that stereoselectively generates 18R-hydroperoxy-EPE [18R-H(p)EPE]. 18R-HEPE is further converted via sequential actions of leucocyte 5-LOX, leading to formation of RvE1. RvE1 acts directly on human platelets to reduce ADP-stimulated platelet aggregation, TX generation, P-selectin mobilization and actin polymerization in a calcium-independent manner. RvE1 counter-regulation of ADP activation is ChemR23 dependent.

Figure 4. Hypothetical scheme for RvE1/ChemR23-dependent signalling in human macrophages

The scheme outlines the key phosphorylation-signalling components with RvE1 and the points of inhibitor action in this system. Inset, representative immunofluorescence of human macrophages phagocytosis of opsonized FITC-zymosan (see [22] for details).

Figure 5. RvE1's selective cellular targets and actions

Scheme of RvE1's actions on specific cells.

Figure 6. Resolution circuitry

(A) Scheme of RvD1 miRNA circuit. RvD1 is generated within inflammatory exudates and acts directly on selective cell types such as monocytes/macrophages. RvD1 actions are via its receptors, ALX or GPR32 to regulate miRNAs, transcription factors, gene expression and cellular function. (B) RvD1 down-regulates miR-219 via its receptors ALX and GPR32, which leads to less 5-LOX protein (C) and reduced LTB₄ generation (D). Adapted from [99]. *P<0.05 compared against vehicle; ^#P<0.05 compared against mock.