Stimulation of Formyl Peptide Receptor-2 by the New Agonist CMC23 Protects against Endotoxin-Induced Neuroinflammatory Response: A Study in Organotypic Hippocampal Cultures

Abstract

A substantial body of evidence demonstrates an association between a malfunction in the resolution of acute inflammation and the development of chronic inflammation. Recently, in this context, the importance of formyl peptide receptor 2 (FPR2) has been underlined. FPR2 activity is modulated by a wide range of endogenous ligands, including specialized pro-resolving mediators (SPMs) (e.g., LXA4 and AT-LXA4) and synthetic ligands. Since SPMs have unfavorable pharmacokinetic properties, we aimed to evaluate the protective and pro-resolving effects of a new potent FPR2 agonist, compound CMC23, in organotypic hippocampal cultures (OHCs) stimulated with lipopolysaccharide (LPS). The protective activity of CMC23 limited the lactate dehydrogenase release in LPSstimulated cultures. This activity was mediated by the interaction with FPR2 as pretreatment with the FPR2 selective antagonist WRW4 abolished CMC23-induced protection. Furthermore, decreased levels of pro-inflammatory IL-1β and IL-6 were observed after CMC23 administration in LPS-treated OHCs. CMC23 also diminished the LPS-induced increase in IL-17A and both IL-23 subunits p19 and p40 in OHCs. Finally, we demonstrated that CMC23 exerts its beneficial impact via the STAT3/SOCS3 signaling pathway since it attenuated the level of phospho-STAT3 and maintained the LPS-induced SOCS3 levels in OHCs. Collectively, our research implies that the new FPR2 agonist CMC23 has beneficial protective and anti-inflammatory properties in nanomolar doses and FPR2 represents a promising target for the enhancement of inflammation resolution.

Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures

“…Nevertheless, the measurement of FPR2 fluorescence demonstrated no complete decrease in FPR2 level, which suggests the presence of this receptor in OHCs after clodronate treatment, although it was significantly reduced. These observations indicate the localisation of FPR2 in other cells in OHCs, probably astrocytes and/or neurons [76].…”