Streptococcus pneumoniae meningitis is a life-threatening bacterial infection of the central nervous system (CNS), and its unfavorable prognosis usually results from an intense inflammatory response. Recent studies have shown that brain-derived neurotrophic factor (BDNF) mediates anti-inflammatory and neuroprotective effects in CNS diseases; however, the distinct contribution of BDNF to pneumococcal meningitis (PM) remains unknown. In this study, we sought to investigate the effects of endogenous BDNF on the inflammatory response and brain damage in experimental PM. We used Camk2a-CreERT2 mice to delete Bdnf from the cerebral cortex and hippocampus, and meningitis was induced by intracisternal infection with S. pneumoniae. Clinical parameters were assessed during acute meningitis. At 24 h post-infection, histopathology, neutrophil granulocytes infiltration, and microglia/macrophage proliferation of brain tissues were evaluated. Additionally, cortical damage and hippocampal apoptosis were assessed using Nissl staining and terminal deoxynucleotidyl transferase dUTP-nick-end labeling (TUNEL), respectively. Pro-inflammatory cytokine levels were determined using real-time polymerase chain reaction (RT-PCR). Key molecules associated with the related signaling pathways were analyzed by RT-PCR and western blot. To investigate the role of microglia/macrophage in infected BDNF conditional knockout mice, GW2580 was used for microglia/macrophage depletion. Here, we, for the first time, found that BDNF conditional knockouts exhibited more profound clinical impairment, pathological severity, and neuron injury and enhanced microglia/macrophage proliferation than were observed in their littermate controls. Furthermore, the BDNF conditional knockouts showed an obviously increase in the expression of pro-inflammatory factors (Tnf-α, Il-1β, and Il-6). Mechanistically, loss of BDNF activated TLR2- and NOD2-mediated downstream nuclear factor kappa B (NF-κB) p65 and p38 mitogen-activated protein kinase (MAPK) pathways associated with S. pneumoniae infection. Furthermore, targeted depletion of microglia/macrophage population decreased the resistance of mice to PM with diminishing neuroinflammation in BDNF conditional knockouts. Our findings suggest that loss of BDNF may enhance the inflammatory response and contribute to brain injury during PM at least partially by modulating TLR2- and NOD2-mediated signaling pathways, thereby providing a potential therapeutic target for future interventions in bacterial meningitis pathologies.

肺炎链球菌脑膜炎是威胁生命的中枢神经系统（CNS）细菌感染，其不良预后通常是由强烈的炎症反应引起的。最近的研究表明，脑源性神经营养因子（BDNF）介导中枢神经系统疾病的抗炎和神经保护作用。然而，BDNF对肺炎球菌性脑膜炎（PM）的独特贡献仍然未知。在这项研究中，我们试图研究内源性BDNF对实验性PM中炎症反应和脑损伤的影响。我们使用Camk2a-CreERT2小鼠删除Bdnf 由大脑皮层和海马区引起，脑膜炎是由脑脊液内感染引起的 肺炎链球菌。在急性脑膜炎期间评估临床参数。感染后24小时，评估了组织病理学，嗜中性粒细胞的浸润以及脑组织的小胶质细胞/巨噬细胞的增殖。此外，分别使用Nissl染色和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）评估皮质损伤和海马细胞凋亡。使用实时聚合酶链反应（RT-PCR）确定促炎细胞因子水平。通过RT-PCR和western blot分析与相关信号通路相关的关键分子。为了研究小胶质细胞/巨噬细胞在感染的BDNF条件敲除小鼠中的作用，GW2580用于小胶质细胞/巨噬细胞的耗竭。在这里，我们首次发现BDNF条件性基因敲除表现出更深刻的临床损伤，病理严重程度，神经元损伤和小胶质细胞/巨噬细胞增殖增强均高于其同窝对照。此外，BDNF条件性基因敲除显示促炎因子的表达明显增加（Tnf-α， 1号β和 6号）。从机制上讲，BDNF激活的TLR2-和NOD2介导的下游核因子kappa B（NF-κB）p65和p38丝裂原激活的蛋白激酶（MAPK）通路的丢失肺炎链球菌感染。此外，小胶质细胞/巨噬细胞群体的有针对性的消耗降低了小鼠对PM的抵抗力，同时减少了BDNF条件性基因敲除中的神经炎症。我们的发现表明，BDNF的丧失可能至少部分地通过调节TLR2和NOD2介导的信号传导通路来增强炎症反应并在PM中造成脑损伤，从而为细菌性脑膜炎病理学的未来干预提供了潜在的治疗靶点。