Abstract
Formyl peptide receptors (Fprs) are a G-protein-coupled receptor family mainly expressed on leukocytes. The activation of Fpr1 and Fpr2 triggers a cascade of signaling events, leading to leukocyte migration, cytokine release, and increased phagocytosis. In this study, we evaluate the effects of the Fpr1 and Fpr2 agonists Ac9-12 and WKYMV, respectively, in carrageenan-induced acute peritonitis and LPS-stimulated macrophages. Peritonitis was induced in male C57BL/6 mice through the intraperitoneal injection of 1 mL of 3% carrageenan solution or saline (control). Pre-treatments with Ac9-12 and WKYMV reduced leukocyte influx to the peritoneal cavity, particularly neutrophils and monocytes, and the release of IL-1β. The addition of the Fpr2 antagonist WRW4 reversed only the anti-inflammatory actions of WKYMV. In vitro, the administration of Boc2 and WRW4 reversed the effects of Ac9-12 and WKYMV, respectively, in the production of IL-6 by LPS-stimulated macrophages. These biological effects of peptides were differently regulated by ERK and p38 signaling pathways. Lipidomic analysis evidenced that Ac9-12 and WKYMV altered the intracellular lipid profile of LPS-stimulated macrophages, revealing an increased concentration of several glycerophospholipids, suggesting regulation of inflammatory pathways triggered by LPS. Overall, our data indicate the therapeutic potential of Ac9-12 and WKYMV via Fpr1 or Fpr2-activation in the inflammatory response and macrophage activation.
Highlights
Formyl peptide receptors (FPRs) represent a family of G protein-coupled receptors related to pro- or anti-inflammatory cellular responses depending on their ligands [1]
We investigated the biological effects of the Ac9-12 tetrapeptide and WKYMV pentapeptide in classic experimental models of carrageenan-induced acute peritonitis in mice [30,31] and macrophage activation by LPS in vitro [27]
The addition of WRW4 reversed the anti-inflammatory actions of WKYMV only, confirming that the pentapeptide preserves the same characteristics as the hexapeptide WKYMVM, and its biological actions occur via activation of Fpr2 [17]
Summary
Formyl peptide receptors (FPRs) represent a family of G protein-coupled receptors related to pro- or anti-inflammatory cellular responses depending on their ligands [1]. The hexapeptide WKYMVM acts as an agonist of FPR2 and FPR3, whereas its diastereomer WKYMVm interacts with the three types of FPR [6,7] These peptides activate NADPH oxidase in neutrophils [18] and promote protective action in experimental models of severe sepsis induced by cecal ligation and puncture in mice [19], as well as in wound closure in diabetic animals, stimulating angiogenesis and immune cell infiltration [20]. Considering that FPRs are expressed in leukocytes and are associated with the control of inflammatory responses, the study of ligands for these receptors is essential to guide new therapeutic strategies in inflammatory diseases In this context, very short peptides have outstanding attributes, such as much easier and economical synthesis, higher mechanical stability, good tissue penetration, and less immunogenicity [21]. To aid in the understanding of the pharmacological effects of these peptides, we monitored the lipidome changes on these systems since the stimulus of inflammatory agents may reflect on changes in the lipid composition of the cells [22]
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