Distinct Signaling Cascades Elicited by Different Formyl Peptide Receptor 2 (FPR2) Agonists

Abstract

The formyl peptide receptor 2 (FPR2) is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR) family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion. In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro- or anti-inflammatory responses. Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (Aβ)-42 and prion protein (Prp)106–126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP)-27, and mitochondrial peptides. Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC), protein kinase C (PKC) isoforms, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, the mitogen-activated protein kinase (MAPK) pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants. FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases. Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2 agonists.

Injectable PLGA microspheres encapsulating WKYMVM peptide for neovascularization

“…Formyl peptide receptor 2 (FPR2) has been shown to stimulates cell proliferation, wound healing, invasion, migration and vessel growth [25]. FPR2 has been identified to be activated by various ligands, which include anti-inflammatory lipids, endogenous peptides, endogenous nonpeptide ligands [26][27][28].…”

Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis

“…37 Interestingly, the chemotactic G-protein-coupled FPRs interact with a menagerie of structurally diverse pro-inflammatory and anti-inflammatory ligands associated with different diseases, including amyloidosis, Alzheimer's disease, prion disease and HIV. 22,38,39 We compared the effect of mFPR1 or mFPR2 deficiency after pneumococcal meningitis.…”

“…While ligands binding to protein-binding domains up-regulate pro-inflammatory transcription factors such as nuclear factor-jB (NF-jB) and activator protein 1 (AP-1), an interaction with the lipid-binding domain inhibits NFjB and AP-1. 37 As a consequence, the activation of the FPRs resulted in a rather pro-inflammatory or anti-inflammatory response. In the context of our results, the lack of the FPRs leads to an increased pro-inflammatory and attenuated anti-inflammatory as well as antimicrobial response.…”

FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model

“…First, we evaluated the vascular reactivity to vasoconstrictor in endothelium-denuded mouse aortic rings since endothelial cells express FPR2/ALX (Koczulla et al, 2003) and we were interested in studying the receptor in the smooth muscle layer. Second, von der Weid et al (2004) study was conducted using a lipid agonist, lipoxin A 4 , whereas in the present work a peptide agonist was used and it is well known that peptide and lipid agonists have distinct effects on FPR2/ALX (reviewed in Cattaneo et al (2013)). Lastly and mostly important, in the present report the effect of FPR2/ALX activation on vascular reactivity was evaluated in an inflammatory context.…”