Investigations for the immunomodulatory and neuroregenerative role of formyl peptide receptors after bacterial meningitis

中枢神经系统(CNS)受到血脑屏障和天然免疫系统的保护，以抵御入侵的病原体。细菌性脑膜炎形式的中枢神经系统感染尽管接受了抗生素治疗，但仍与高死亡率和长期后遗症有关。对于病原体的检测，由先天免疫细胞模式识别受体负责。甲酰肽受体家族是PRR的一个重要代表。趋化G蛋白偶联受体是由原核细菌细胞壁的N-甲酰基多肽或在组织损伤背景下释放的线粒体成分激活的。此外，广泛的促炎或抗炎配体激活了fpr。有趣的是，研究表明，FPR介导了内源性蛋白Annexin A1的抗炎活性。对于Annexin A1及其生物活性片段Ac2-26，在多发性硬化症的病程中检测到炎症过程的积极影响。我们之前的工作表明，与野生型小鼠相比，细菌性脑膜炎后FPR缺陷小鼠的死亡率和炎症反应增加。在目前的应用中，应该在肺炎链球菌脑膜炎的小鼠模型中研究FPR的免疫调节潜力，因为炎症反应在急性和长期损害的发展中都起着至关重要的作用。为此，在肺炎球菌脑膜炎诱导后，野生型和受体缺陷小鼠被注射Ac2-26。随后，炎症反应的调节和神经元损伤的再生应以海马神经发生的形式为特征。组织学改变可能的功能后果应通过神经心理测试(Morris水迷宫)来检查。体内研究辅之以体外研究，以便更好地了解不同配体之间在信号转导途径方面的差异及其对炎症反应的相关影响。此外，我们计划对Ac2-26对整个生物体的影响进行广泛的研究。收到的应用结果可能为细菌性脑膜炎的新辅助治疗策略提供新的方法。

The central nervous system (CNS) is protected by the blood-brain barrier and the innate immune system against invading pathogens. An infection of the CNS in the form of bacterial meningitis is despite antibiotic therapy still associated with a high mortality rate and long-term sequelae. For the detection of the pathogens by the innate immune cells pattern recognition receptors are responsible. An important representative of the PRR is the family of formyl peptide receptors (FPR). The chemotactic G-protein-coupled receptors are activated by n-formyl peptides of prokaryotic bacterial cell wall or by mitochondrial components released in the context of tissue injury. Furthermore, the FPR are activated by a broad spectrum of pro- or anti-inflammatory ligands. Interestingly, it was shown that the FPRs are mediated the anti-inflammatory activity of the endogenous protein annexin A1. For annexin A1 and its bioactive fragment Ac2-26, a positive influence of the inflammatory processes in the course of multiple sclerosis was detected. Our previous work shown for the FPR-deficient mice an increase of mortality and inflammatory response after bacterial meningitis compared to wildtype mice. With the present application, the immunomodulatory potential of the FPR should be investigated in a mouse model of Streptococcus pneumoniae meningitis, because the inflammatory response an essential role in the development of both acute and long-term damage is attributed. For this purpose, wildtype and receptor-deficient mice are intraperitoneally injected with Ac2-26 after the induction of pneumococcal meningitis. Subsequently, the modulation of the inflammatory response and regeneration of the neuronal damage should be characterized in the form of hippocampal neurogenesis. Possible functional consequences of histological changes should be checked by means of neuropsychological test (Morris Water Maze). The in vivo studies are complemented by in vitro studies in order to better understand the differences between the different ligands with respect to their signal transduction pathways and the associated effect on the inflammatory response. In addition, we plan to perform a broad study of the Ac2-26 effect on the whole organism. The received findings of the application could provide new approaches for novel adjuvant treatment strategies for bacterial meningitis.