Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.

中文翻译：

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甲酰肽受体激动剂 Ac2-26 减轻肺炎球菌脑膜炎小鼠模型的神经炎症

细菌性脑膜炎仍然是导致严重神经功能障碍的一个原因。大脑受到血脑屏障和先天免疫系统的保护，免受病原体的侵袭。入侵的病原体被模式识别受体识别，包括由中枢神经系统免疫细胞表达的 G 蛋白偶联甲酰肽受体 (FPR)。FPR 显示出广泛的配体，包括促炎和抗炎配体。在这里，我们研究了膜联蛋白 A1 模拟肽 Ac2-26 在肺炎球菌脑膜炎小鼠模型中的作用。野生型 (WT) 和 Fpr1 和 Fpr2 缺陷小鼠鞘内感染肺炎链球菌 D39（2 型）。随后，不同的小鼠组在感染后 2、8 和 24 小时通过腹腔注射 Ac2-26（1 毫克/千克体重）进行治疗。感染后 30 小时，通过免疫组织化学和实时逆转录聚合酶链反应 (RT-PCR) 分析不同大脑区域的炎症程度。Ac2-26 处理的 WT 小鼠表现出不太严重的中性粒细胞浸润，同时海马结构和皮质中促炎性神经胶质细胞反应的诱导减少。虽然脑膜炎在 Ac2-26 治疗的 Fpr1 缺陷小鼠中得到改善，但在 Fpr2 缺陷小鼠中未观察到这种保护作用。与 Ac2-26 治疗无关，与 Fpr1 缺陷小鼠相比，Fpr2 缺陷小鼠的炎症更严重。总之，该研究证明了 Ac2-26 在细菌性脑膜炎模型中的抗炎特性，该特性通过 FPR2 而不是 FPR1 介导。