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

细菌性脑膜炎后甲酰基肽受体的免疫调节和神经再生作用的研究

• 批准号: 316888920
• 负责人: Professor Dr. Lars-Ove Brandenburg
• 金额: --
• 依托单位: Klinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/316888920?language=en
• 关键词: Investigations; immunomodulatory; neuroregenerative; role; formyl

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.

中枢神经系统（CNS）受到血脑屏障和先天免疫系统的保护，以抵御入侵的病原体。尽管抗生素治疗，细菌性脑膜炎形式的CNS感染仍然与高死亡率和长期后遗症相关。对于通过先天免疫细胞检测病原体，模式识别受体负责。PRR的一个重要代表是甲酰肽受体（FPR）家族。趋化性G蛋白偶联受体被原核细菌细胞壁的N-甲酰肽或在组织损伤的背景下释放的线粒体组分激活。此外，FPR被广谱的促炎或抗炎配体激活。有趣的是，研究表明FPR介导内源性蛋白膜联蛋白A1的抗炎活性。对于膜联蛋白A1及其生物活性片段Ac 2 -26，检测到多发性硬化过程中炎症过程的积极影响。我们以前的工作表明，与野生型小鼠相比，FPR缺陷小鼠在细菌性脑膜炎后死亡率和炎症反应增加。对于本申请，应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伤的发展中起重要作用。为此，在诱导肺炎球菌脑膜炎后，向野生型和受体缺陷型小鼠腹膜内注射Ac 2 -26。随后，炎症反应的调制和神经元损伤的再生应以海马神经发生的形式为特征。组织学变化可能的功能后果应通过神经心理学测试（Morris水迷宫）进行检查。为了更好地了解不同配体在其信号转导途径和对炎症反应的相关影响方面的差异，体内研究得到了体外研究的补充。此外，我们计划对Ac 2 -26对整个生物体的影响进行广泛的研究。收到的申请结果可以为细菌性脑膜炎的新辅助治疗策略提供新的方法。