Proresolving Lipid Mediators and Mechanisms in the Resolution of Acute Inflammation

Abstract

SUMMARY Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defence. Indeed the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review we explore the immunological consequences of these omega-3-derived specialized pro-resolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation.

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

“…Resolution is an active process involving the production of molecules that signal through specific cell-surface receptors to temper inflammation, enhance efferocytosis, and repair tissue damage without compromising host defense (1,(6)(7)(8). Specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids, represent a key family of resolution effectors.…”

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

“…Unravelling the mediators that provide tissue protection and developing peptide-based drugs targeted at the resolution phase of inflammation is an exciting concept [38,39]. Amongst a host of such mediators are the melanocortins.…”

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

“…The mechanism of how free arachidonate, the substrate for 15-lipoxygenase, is generated under these conditions requires further investigation. 15-lipoxgenases are also implicated in the generation of proresolving lipid mediators form arachidonic, eicosapentaenoic, or docosahexaenoic acid (39). However, this mostly requires transcellular lipid modification and is unlikely to play a major role in IL-4-stimulated macrophages when ALOX5 and ALOX15 are regulated opposed to each other.…”