Abstract:

There is much recent interest in the role of the anti-inflammatory molecules and their receptors in the normal brain and in neurological disorders. The formyl peptide receptor (FPR) subfamily of G protein-coupled receptors play important roles in these processes. Binding to specific peptides triggers activation of FPRs, leading to signalling events that regulate inflammatory responses. One member of this subfamily of receptors is FPR2, also known as ALX (the lipoxin A4 (LXA4) receptor). FPR2 is specifically activated by LXA4 and resolvin D1 (RvD1). LXA4 is an anti-inflammatory molecule produced by the action of lipoxygenases on arachidonic acid, while RvD1 is produced by the action of lipoxygenases on docosahexaenoic acid, a component of fish oil. Activation of FPR2 by LXA4 or RvD1 triggers downstream signalling cascades, e.g., inhibition of calcium-calmodulin dependent protein kinase and p38 mitogen-activated protein kinase phosphorylation, leading to a reduction in inflammatory responses. Annexin A1 (ANXA1) is another molecule which could interact with FPR2. A Ca 2+ -dependent phospholipid-binding protein, ANXA1 suppresses phospholipase A 2 activity to reduce arachidonic acid and eicosanoid production and decrease leukocyte inflammatory events such as cell migration, chemotaxis, phagocytosis and respiratory burst. While many studies have shown that binding to FPR2 is a chemotactic signal to attract macrophages to the site of tissue injury, other studies have highlighted that it is part of an anti-inflammatory process. For example, from some of the studies detailed below, it seems that activation of this receptor does not itself cause further production of pro-inflammatory mediators by macrophages. Instead, FPR2 appears to attract macrophages and other immune cells to the site of tissue injury to initiate a “quiet mopping-up process”to resolve inflammation.