Biosynthesis of specialized proresolving mediators (SPMs)

To prevent the onset of chronic inflammation, a lipid mediator class switch is thought to occur from the initial actions of pro-inflammatory lipid mediators to the anti-inflammatory and pro-resolving actions of lipoxins, resolvins, protectins and maresins (collectively called specialized proresolving mediators (SPMs)). Nanopicogram quantities of different lipid mediators are generated at different times during the evolution of the inflammatory response and these mediators coincide with distinct cellular events. The class switch activates leukocyte translational regulation of the enzymes required to produce pro-resolving lipid mediators. Each family of these PSMs exert specialized actions, including blocking neutrophil recruitment, promoting the recruitment and activation of monocytes, as well as mediating the nonphlogistic phagocytosis and lymphatic clearance of apoptotic neutrophils by activated macrophages (ie without inducing inflammation) and mediating tissue regeneration. Eventually, through the combined actions of these mediators, the resolution of inflammation is completed and homeostasis is reached (Serhan 2010, Bannenberg & Serhan 2010, Freire & Van Dyke 2013, Serhan et al. 2014).

SPMs are derived from polyunsaturated fatty acids (PUFAs). PUFAs of the ω-3 series are essential nutrients since they cannot be produced by humans and are primarily found in dietary fish oils and in plants. The ω-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPAn-3) circulate in the bloodstream after dietary intake and are easily incorporated into cellular membranes in a time- and dose-dependent manner, as well as being present in inflammatory exudates. They can be mobilised by phospholipase A2 from cellular membranes on injury or infection when they are converted to exudate SPMs to interact with local immune cells. EPA is the source for E-series resolvins while DHA is the source for D-series resolvins, protectins, maresins and sulfido conjugates in tissue regeneration mediators. The ω-6 fatty acid arachidonic acid (AA) is the source for lipoxins. ω-3 or ω-6 PUFA docosapentaenoic acids (DPAn-3 and DPAn-6) are the sources of DPA-derived resolvins, protectins and maresins. Aspirin can also trigger the production of epimeric SPMs via acetylated PTGS2 (prostaglandin G/H synthase, COX2). Combinations of oxidation, reduction and hydrolysis can generate numerous SPMs. Electrophilic oxo-derivatives of ω-3 PUFAs are a class of oxidised derivatives that are generated in macrophages and neutrophils by the actions of 5-lipoxygenase, cyclooxygenase-2 and acetylated cyclooxygenase-2, followed by dehydrogenation. Being electrophilic, oxo-derivative SPMs reversibly bind to nucleophilic residues on target proteins, triggering the activation of cytoprotective pathways. The pathways in this section describe the biosynthesis of these SPMs.