Denise Pajonczyk, Merle F. Sternschulte, Oliver Soehnlein, Marcel Bermudez, Carsten A. Raabe, Ursula Rescher
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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.</p>\n </section>\n \n <section>\n \n <h3> Experimental Approach</h3>\n \n <p>We deduced EC<sub>50</sub> and E<sub>max</sub> 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.</p>\n </section>\n \n <section>\n \n <h3> Key results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Conclusion and Implications</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> LINKED ARTICLES</h3>\n \n <p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc</p>\n </section>\n </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 20","pages":"4911-4925"},"PeriodicalIF":7.5000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.17334","citationCount":"0","resultStr":"{\"title\":\"Comparative analysis of formyl peptide receptor 1 and formyl peptide receptor 2 reveals shared and preserved signalling profiles\",\"authors\":\"Denise Pajonczyk, Merle F. Sternschulte, Oliver Soehnlein, Marcel Bermudez, Carsten A. Raabe, Ursula Rescher\",\"doi\":\"10.1111/bph.17334\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Background and Purpose</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Experimental Approach</h3>\\n \\n <p>We deduced EC<sub>50</sub> and E<sub>max</sub> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key results</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion and Implications</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> LINKED ARTICLES</h3>\\n \\n <p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. 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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 EC50 and Emax 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.
LINKED ARTICLES
This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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