Localisation of Formyl-Peptide Receptor 2 in the Rat Central Nervous System and Its Role in Axonal and Dendritic Outgrowth

Christabel Fung-Yih Ho,Saravanan Gunaseelan,Joled Kong-Ze Koh,John Jia-En Chua,Yi-Hua Low,Wei-Yi Ong,Nadia Binte Ismail,Yee-Kong Ng

doi:10.1007/s11064-018-2573-0

Abstract

Arachidonic acid and docosahexaenoic acid (DHA) released by the action of phospholipases A2 (PLA2) on membrane phospholipids may be metabolized by lipoxygenases to the anti-inflammatory mediators lipoxin A4 (LXA4) and resolvin D1 (RvD1), and these can bind to a common receptor, formyl-peptide receptor 2 (FPR2). The contribution of this receptor to axonal or dendritic outgrowth is unknown. The present study was carried out to elucidate the distribution of FPR2 in the rat CNS and its role in outgrowth of neuronal processes. FPR2 mRNA expression was greatest in the brainstem, followed by the spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The brainstem and spinal cord also contained high levels of FPR2 protein. The cerebral neocortex was moderately immunolabelled for FPR2, with staining mostly present as puncta in the neuropil. Dentate granule neurons and their axons (mossy fibres) in the hippocampus were very densely labelled. The cerebellar cortex was lightly stained, but the deep cerebellar nuclei, inferior olivary nucleus, vestibular nuclei, spinal trigeminal nucleus and dorsal horn of the spinal cord were densely labelled. Electron microscopy of the prefrontal cortex showed FPR2 immunolabel mostly in immature axon terminals or ‘pre-terminals’, that did not form synapses with dendrites. Treatment of primary hippocampal neurons with the FPR2 inhibitors, PBP10 or WRW4, resulted in reduced lengths of axons and dendrites. The CNS distribution of FPR2 suggests important functions in learning and memory, balance and nociception. This might be due to an effect of FPR2 in mediating arachidonic acid/LXA4 or DHA/RvD1-induced axonal or dendritic outgrowth.

Highlights

There has been much recent interest in the role of lipid mediators in neuronal signalling
The relative expression levels of formyl-peptide receptor 2 (FPR2) mRNA in the brain and spinal cord were determined by real-time RT-PCR (Fig. 1)
Real-time RT-PCR results indicate that FPR2 mRNA is generally present in all brain regions, with higher expression in the brainstem and spinal cord than the forebrain

Summary

Introduction

There has been much recent interest in the role of lipid mediators in neuronal signalling. Neurochemical Research (2018) 43:1587–1598 potent pro-resolvin lipid mediator that limits polymorphonuclear leukocyte recruitment to inflammatory loci [10], and neuroprotectin D1 reduces expression of pro-inflammatory factors and protects human retinal pigment epithelial cells from oxidative stress [11]. Both LXA4 and RvD1 activate a G-protein coupled receptor (GPCR), formyl-peptide receptor 2 (FPR2) ( known as FPR-L1) [12]. The latter is a member of the FPR family of seven transmembrane GPCRs originally identified as anti-microbial receptors on the surface of neutrophils and monocytes/macrophages [13]

Methods

Results

Conclusion