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

ACS Chem Neurosci. 2023 Oct 18;14(20):3869-3882. doi: 10.1021/acschemneuro.3c00525. Epub 2023 Sep 29.

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 LPS-stimulated 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.

Keywords: formyl peptide receptor 2; hippocampus; intracellular pathways; lipopolysaccharide; neuroinflammation; ureidopropanamide agonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endotoxins
  • Hippocampus / metabolism
  • Humans
  • Lipopolysaccharides / toxicity
  • Neuroinflammatory Diseases* / chemically induced
  • Neuroinflammatory Diseases* / drug therapy
  • Receptors, Formyl Peptide* / agonists

Substances

  • Endotoxins
  • Lipopolysaccharides
  • Receptors, Formyl Peptide