Pro-resolving lipid mediators are leads for resolution physiology

Abstract

Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.

Figure 1. Lipid mediators in the acute inflammatory response, resolution and other outcomes

LM play pivotal roles in the vascular response and leukocyte trafficking, from initiation to resolution. Eicosanoids are critical in initiating the cardinal signs of inflammation (upper left). The lipoxins, resolvins, protectins and maresins, specialized proresolving mediators (SPM), are produced in self-limited responses (Fig. 2). SPM stimulate cellular events that counter-regulate pro-inflammatory mediators and regulate PMN, monocyte and macrophage response, leading to resolution. Depicted are some pro-resolving actions in leukocyte trafficking (neutrophil-monocyte sequence), lipid mediator class switching and efferocytosis of apoptotic PMN that must occur in resolving exudates for restoration of normal structure and homeostasis. In addition to the release of n-3 substrate from phospholipid stores, omega-3 substrates can enter mouse exudates via edema from peripheral blood. SPM enhance efferocytosis, stimulate signs of resolution (lower right) and signal to adaptive immunity via lymphocytes. Failed resolution may lead to enhanced prostaglandins and leukotrienes, chronic inflammation and fibrosis. SPM counterregulate pro-inflammatory chemical mediators, reducing magnitude and duration of inflammation, and stimulate reepithelialization, wound healing, and tissue regeneration in model organisms.

Figure 2. SPM production in resolving inflammatory exudates

Upper panel depicts a typical self-limited acute inflammatory response time course encountered in experimental settings from initiation (time 0) to resolution: edema, neutrophilic infiltration and nonphlogistic recruitment of monocytes/macrophages. Biosynthesis of SPM occurs temporally in resolving exudates. Non-phlogistic recruitment of monocytes and macrophages is required for homeostasis, repair and regeneration of injured tissues. Lower panel, Resolution n-3 metabolome. Biosynthesis of resolvins, protectins and maresins from EPA and DHA with the main bioactive structures from each family (see Box 1 and refs. ^, for details on biosynthetic mechanisms and stereochemical assignments of the bioactive products). Each SPM stimulates macrophage switching to M2 phenotype and is produced by human neutrophils, apoptotic PMN and macrophages.