Role of formyl peptide receptor 2 (FPR2) in the normal brain and in neurological conditions

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) (Pirault and Bäck, 2018). 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-dependent phospholipid-binding protein, ANXA1 suppresses phospholipase A2 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 (summarized in Figure 1), 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. In recent years, the FPR2 signaling pathway has also been shown to be utilized by the brain for a range of normal activities (Figure 1). Interestingly, FPR1 and FPR2 are expressed in neural stem cells and are involved in promoting their migration and differentiation into neurons (Wang et al., 2016). FPR2 is expressed in many parts of the adult rat central nervous system. The cerebral neocortex is moderately immunolabelled for FPR2, while dentate granule neurons and their axons (mossy fibres) in the hippocampus, the deep cerebellar nuclei, inferior olivary nucleus, vestibular nuclei, spinal trigeminal nucleus and dorsal horn of the spinal cord are densely labeled. FPR2 immunolabelled processes have the appearance of immature processes under electron microscopy, and inhibition of FPR2 results in reduced length of axons and dendrites in cultured hippocampal neurons (Ho et al., 2018). Moreover, FPR2 neuronal processes were found to have features of growth cones (Korimová et al., 2018). The neurite-promoting function of anti-inflammatory molecules and their receptors such as FPR2 may be important for the day-to-day functions of the central nervous system, such as synaptic plasticity, learning and memory. This system may be overwhelmed during conditions of neuroinflammation, leading to loss of neuronal functions. In this context, it is interesting to note that there is much interest in the role of FPR2 in Alzheimer’s disease. Early studies have shown a high level of expression of FPR2 in amyloid plaques of Alzheimer’s disease patients and that the amyloid β peptide (Aβ) is a chemotactic agonist for FPR2 receptor. Aβ binding to FPR2 is followed by internalization of Aβ/FPR2 complexes and leads to the accumulation and activation of mononuclear phagocytes (monocytes and microglia) (Cui et al., 2002). Other studies have highlighted the beneficial effects of triggering early minor activation of microglia to mediate soluble Aβ clearance and resolution of neuroinflammation. For example, ANXA1, acting via FPR2 receptors, reduces Aβ levels by enhancing its degradation by neprilysin in N2a cells and stimulating Aβ phagocytosis by microglia. Moreover, ANXA1 prevents Aβ-induced secretion of microglial inflammatory mediators