The N-formyl peptide receptors: much more than chemoattractant receptors. Relevance in health and disease

Abstract

Pattern Recognition Receptors (PRRs) are a superfamily of receptors that detect molecular structures typical for pathogens and damaged cells and play a crucial role in the proper function of the innate immune system. A particular subgroup of membrane-bound PRRs is represented by the N-formyl peptide receptors (FPRs) that consist of transmembrane G-protein coupled receptors involved in inflammatory responses. FPRs were initially described in immune cells as transducers of chemotactic signals in phagocytes that react to tissue injury. Subsequently, FPRs were also identified in a wide variety of cell types, including cancer cells. Beyond broad cellular distribution, FPRs are also characterized by the ability to bind a variety of ligands with different chemical and biological properties, ranging from natural peptides to synthetic compounds. The binding of FPRs to specific agonists induces a cascade of functional biological events, such as cell proliferation, migration, angiogenesis, and oxidative stress. From all this evidence, it becomes clear that FPRs are multifaceted receptors involved in several pathophysiological processes associated with inflammation. In this review, we provide a comprehensive molecular description of structure-function relationship of FPRs and their pivotal role in the host defense, highlighting the regulatory functions in both the initiation and resolution of inflammation. In addition to their activity as PRRs during innate immune response, we focus on their involvement in pathological conditions, including chronic inflammatory disease, neurodegenerative disorders, and cancer, with special emphasis on FPR targeting as promising therapeutic strategies in the era of precision medicine.

Keywords: G-protein coupled receptors; N-formyl peptide receptors; chemoattractant receptors; inflammation; receptor structure-function.

Figure 1

Pro-inflammatory and pro-tumorigenic signaling pathways mediated by FPRs. (1) FPR1 recognize microbe- derived formylated peptides, including E. Coli-derived fMLF, Salmonella-derived fMAMKKL, Staphylococcus-derived fMIYYCK, Listeria-derived fMKKIML; HIV-derived non formylated peptides gp41; soluble Urokinase Receptor (suPAR); TAFA chemokine like family member 4 (TAFA4); WKYMVm (Trp-Lys-Tyr-Met-Val-D-Met) synthetic hexapeptide. (2) FPR2 agonists with pro-inflammatory effects include fMLF, Serum Amyloid A (SAA), antimicrobial peptide LL-37, suPAR, and WKYMVm synthetic peptide. (3) FPR3, with significantly basal levels of phosphorylation, binds F2L, a peptide derived from heme-binding protein, suPAR, and WKYMVm synthetic peptide. (4) FPR3 is found mainly distributed in early and late endosome during acute inflammation, suggesting FPR3 continuous recycling following endocytosis in response to pro-inflammatory stimuli. (5) Pro-tumorigenic effects of FPRs are mediated in part by transactivation of epidermal growth factor (EGF) receptor (EGFR) and membrane-anchored uPAR. FPRs/EGFR and FPRs/uPAR crosstalk plays a central role in cell proliferation, matrix deposition, epithelial-mesenchymal transition, ROS production, and pro-inflammatory cytokine signaling. (6) The activation of FPRs from binding pro-inflammatory ligands results in the dissociation of the Gα from the Gβγ subunit. α subunit activates the Ras superfamily, which contribute to activation of the MAPK pathways, p38, and ERK1/2. FPR-mediated ERK activation results in c-Myc Ser62 phosphorylation that has been observed in numerous cancer cells. βγ subunits activate PLCβ, resulting in calcium release from intracellular stores, PKC and PI3K which further contribute to activation of Rac1 GTPase. Rac1 induces the assembly and activation of NADPH oxidase to produce reactive oxygen species (ROS), Rho GTPases to facilitate cancer cell metastasis by regulating actin and proteins associated with cell migration and invasion, and Akt/mTOR axis to enhance cyclin D1 and cell cycle progression. (7) The effects of pro-inflammatory and pro-tumorigenic ligands culminate in the activation of transcription factors including STAT, VEGF, NF-κB, and CXCL8. (8) Pro-inflammatory agonist peptides promote the production of pro-inflammatory cytokines, including IL-6, IL-1β, TNF-α, and IFN-γ.

Figure 2

Anti-inflammatory and pro-resolving signaling pathways mediated by FPRs. (1) FPR1 agonists with anti-inflammatory effects include Annexin A1 (ANXA1) and N-terminal peptide of ANXA1, Ac2-26. (2) FPR1 agonists with anti-inflammatory effects include ANXA1, Ac2-26, lipid mediators Lipoxin A4 (LXA4) and Resolvin D1 (RvD1), Hp2-20 peptide of Helicobacter pylori, Vasoactive intestinal peptide (VIP), WKYMVm synthetic peptide, and humanin, a recently identified neuroprotective factor. (3) FPR3 is constitutively internalized and binds humanin and F2L. (4) FPR1/FPR2 heterodimers and FPR2 homodimers elicit pro-resolving and pro-inflammatory effects. (5) Pro-resolution and anti-inflammatory pathways start with β-arrestin 2 recruitment, which induces receptor desensitization and internalization and G-protein independent signaling. β-arrestin 2 promote bcl-xL expression, leading to cell survival, cAMP-mediated signaling, and p38 MAPK phosphorylation. (6) FPR2 internalization is crucial for the resolution of inflammation as the internalized receptor inhibits NF-κB activity. (7) The activation of anti-inflammatory and pro-resolving pathways mediated by FPRs induces the transcription of cAMP response element-binding protein (CREB), peroxisome proliferator-activated receptor (PPARγ), and nuclear factor erythroid 2–related factor 2 (NRF2). (8) FPR pro-resolving agonists upregulate anti-inflammatory factors, including IL-10, and block the release of pro-inflammatory cytokines, such as IL-6, IL-1β, TNF-α, and IFN-γ.