Comparative analysis of formyl peptide receptor 1 and formyl peptide receptor 2 reveals shared and preserved signalling profiles

Background and Purpose The pattern recognition receptors, formyl peptide receptors, FPR1 and FPR2, are G protein‐coupled receptors that recognize many different pathogen‐ and host‐derived ligands. While FPR1 conveys pro‐inflammatory signals, FPR2 is linked with pro‐resolving outcomes. To analyse how the two very similar FPRs exert opposite effects in modulating inflammatory responses despite their high homology, a shared expression profile on immune cells and an overlapping ligand repertoire, we questioned whether the signalling profile differs between these two receptors. Experimental Approach We deduced EC 50 and E max values for synthetic, pathogen‐derived and host‐derived peptide agonists for both FPR1 and FPR2 and analysed them within the framework of biased signalling. We furthermore investigated whether FPR isoform‐specific agonists affect the ex vivo lifespan of human neutrophils. Key results The FPRs share a core signature across signalling pathways. Whereas the synthetic WKYMVm and formylated peptides acted as potent agonists at FPR1, and at FPR2, only WKYMVm was a full agonist. Natural FPR2 agonists, irrespective of N‐terminal formylation, displayed lower activity ratios, suggesting an underutilized signalling potential of this receptor. FPR2 agonism did not counteract LPS‐induced neutrophil survival, indicating that FPR2 activation per se is not linked with a pro‐resolving function. Conclusion and Implications Activation of FPR1 and FPR2 by a representative agonist panel revealed a lack of a receptor‐specific signalling texture, challenging assumptions about distinct inflammatory profiles linked to specific receptor isoforms, signalling patterns or agonist classes. These conclusions are restricted to the specific agonists and signalling pathways examined.