INTRODUCTION: A lot of evidence demonstrates that Formyl-Peptide Receptor 2 (FPR2), fulfills various functions in the brain. Interestingly, based on agonist biased, this receptor can induce pro- and anti-inflammatory responses depending on the chemical structure of ligands. Recently, we have synthesized a new class of non-peptidic compounds that can activate.AIM: The present study aimed to determine the anti-inflammatory effect of FPR2 agonists: IG-4 in microglial cell cultures isolated from the brains of adult mice which are a human amyloid precursor protein (hAPP) knock-in mouse model of Alzheimer's Disease. Moreover, we used a model of inflammation based on bacterial endotoxin–lipopolysaccharide (LPS) stimulation.METHODS: Microglial cells were prepared from the 9-month-old APPNL-F/NL-F mice. The cells were pretreated for 1 h with FPR2 agonist- IG-4 (1 μM) and then stimulated for 24 h with LPS (100 ng/ml). After that, we measured the cell death parameters using LDH assay. Moreover, we evaluated the secretion of NO by a Griess reaction and the production of pro-inflammatory cytokine – IL-1β using ELISA kits.RESULTS: Analysis of IG-4 showed that it suppressed the LPS-evoked LDH and NO release in microglial cell cultures. It was also able to significantly reduce the production of pro-inflammatory mediators – IL-1β when microglial cells were stimulated with LPS.CONCLUSION: Our novel discoveries greatly expanded the current understanding of the pro-resolving role of formyl-peptide receptor activation and opened new therapeutic perspectives in the treatment of CNS disorders characterized by neuroinflammation. Supported by the grant no. 2021/43/B/NZ4/01133, National Science Centre, Poland (Task 1).