Protectins and maresins: New pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome

Abstract

Acute inflammatory responses are protective, yet without timely resolution can lead to chronic inflammation and organ fibrosis. A systems approach to investigate self-limited (self-resolving) inflammatory exudates in mice and structural elucidation uncovered novel resolution phase mediators in vivo that stimulate endogenous resolution mechanisms in inflammation. Resolving inflammatory exudates and human leukocytes utilize DHA and other n-3 EFA to produce three structurally distinct families of potent di- and trihydroxy-containing products, with several stereospecific potent mediators in each family. Given their potent and stereoselective picogram actions, specific members of these new families of mediators from the DHA metabolome were named D-series resolvins (Resolvin D1 to Resolvin D6), protectins (including protectin D1-neuroprotectin D1), and maresins (MaR1 and MaR2). In this review, we focus on a) biosynthesis of protectins and maresins as anti-inflammatory-pro-resolving mediators; b) their complete stereochemical assignments and actions in vivo in disease models. Each pathway involves the biosynthesis of epoxide-containing intermediates produced from hydroperoxy-containing precursors from human leukocytes and within exudates. Also, aspirin triggers an endogenous DHA metabolome that biosynthesizes potent products in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. Identification and structural elucidation of these new families of bioactive mediators in resolution has opened the possibility of diverse patho-physiologic actions in several processes including infection, inflammatory pain, tissue regeneration, neuroprotection-neurodegenerative disorders, wound healing, and others. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".

Keywords: Eicosanoid; LC–MS–MS-based targeted lipid mediator metabolomics; Leukocyte; Lipid mediator; Resolvin.

Figure 1. Specialized Pro-Resolving Lipid Mediator Families Biosynthesized From Their Parent Polyunsaturated Fatty Acids

Resolving exudates utilize essential fatty acids such as DHA to form several structurally distinct groups of specialized proresolving mediators that promote clearance and resolution.

Figure 2. Protectin Biosynthetic Pathway

PD1 produced enzymatically from the 16S, 17S epoxy protectin (pictured in a tentative double bond geometry) was confirmed by epoxide trapping experiments. Non-enzymatic hydrolysis of this epoxide intermediate formed two minor products, the all-trans-triene isomer and vicinal 16, 17S diol. The 10S, 17S double dioxygenation pathway and product occur by sequential actions of two lipoxygenation enzymes as demonstrated in cell incubation and isolated enzymes carried out under an enriched atmosphere of ¹⁸O₂. See text for further details.

Figure 3. Aspirin-Triggered (AT) Protectin Biosynthetic Pathway

An additional pathway via aspirin-acetylated COX-2 enzyme gives rise to inversion of stereochemistry at the 17 position to afford the 17R hydroxyl-containing products. The 17R hydroperoxide precursor can undergo enzymatic epoxidation to the 16R, 17R epoxy protectin. This epoxide is then enzymatically hydrolyzed to the 10R, 17R AT-(NPD1/PD1).

Figure 4. Maresin Biosynthetic Pathway

The biosynthesis of MaR1 is formed through 13, 14 epoxide intermediate confirmed by alcohol trapping products. In addition, several isomers formed through alternative pathways were confirmed by matching studies of synthetic compounds made in a stereo-controlled manner. See text for further details.

Figure 5. Comparison of Mechanisms in Protectin and Maresin Biosynthesis

Proton abstraction of the 17S hydroperoxide pictured above or the 14S hydroperoxide pictured below forms the 16S, 17S epoxide and 13S, 14S epoxide respectively. Enzymecatalyzed formation of a rigid carbonium cation intermediate from the respective epoxides undergoes a stereospecific attack by oxygen from a water molecule. This enzyme-catalyzed hydrolysis affords predominantly the R insertion of oxygen from water at the 10 position in the upper protectin pathway and at the 7 position in the lower maresin pathway.