Effects of Formyl Peptide Receptor Agonists Ac 9-12 and WKYMV in In Vivo and In Vitro Acute Inflammatory Experimental Models

• Published in: Cells (Basel, Switzerland) Switzerland), 2022-01, Vol.11 (2)
• Main Authors: Lice, Izabella, Sanches, José Marcos, Correia-Silva, Rebeca D, Corrêa, Mab P, Icimoto, Marcelo Y, Silva, Alex A R, Sánchez-Vinces, Salvador, Porcari, Andreia M, Moreira, Vanessa, Gil, Cristiane D
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement - drug effects; Cytokines - metabolism; Disease Models, Animal; Inflammation - pathology; Interleukin-1beta - metabolism; Leukocytes - cytology; Leukocytes - drug effects; Lipidomics; Lipopolysaccharides - pharmacology; Macrophage Activation - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Oligopeptides - pharmacology; Peptides - pharmacology; Peritonitis - pathology; RAW 264.7 Cells; Receptors, Formyl Peptide - agonists; Receptors, Formyl Peptide - metabolism
• ISSN: 2073-4409
• DOI: 10.3390/cells11020228

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 Ac 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 Ac 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 Ac 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 Ac 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 Ac and WKYMV via Fpr1 or Fpr2-activation in the inflammatory response and macrophage activation.