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.
摘要：
大量证据表明，急性炎症的解决与慢性炎症的发展之间存在关联。最近,在这种情况下，已经强调了甲酰肽受体2(FPR2)的重要性。FPR2活性受多种内源性配体的调节，包括专门的亲解决调解员(SPM)(例如，LXA4和AT-LXA4)和合成配体。由于SPM具有不利的药代动力学特性，我们的目的是评估一种新型有效的FPR2激动剂的保护和促进解决作用，化合物CMC23，在脂多糖（LPS）刺激的器官型海马培养物（OHC）中。CMC23的保护活性限制了LPS刺激的培养物中乳酸脱氢酶的释放。该活性是由与FPR2的相互作用介导的，因为用FPR2选择性拮抗剂WRW4预处理消除了CMC23诱导的保护作用。此外，在LPS处理的OHC中施用CMC23后观察到促炎性IL-1β和IL-6水平降低。CMC23还减少了LPS诱导的OHC中IL-17A和IL-23亚基p19和p40的增加。最后,我们证明了CMC23通过STAT3/SOCS3信号通路发挥其有益的影响,因为它减弱了磷酸化STAT3的水平,并维持了LPS诱导的OHC中SOCS3的水平.总的来说，我们的研究表明,新的FPR2激动剂CMC23在纳摩尔剂量下具有有益的保护和抗炎特性,FPR2是增强炎症消退的有希望的靶标.
