Toll-like receptor 2 (TLR2) is a primary sensor for pathogens, including those derived from gram-positive bacteria. It can also mediate the effects of endogenous inflammatory signals such as β-amyloid peptide (Aβ), thus promoting the microglial activation and subsequent neuronal dysfunction, characteristic of chronic neuroinflammatory conditions. More recently, a role for TLR2 has been proposed in the pathogenesis of disorders associated with acute inflammation, including anxiety and depression. The current study aims to characterise the acute effects of the TLR2 agonist lipoteichoic acid (LTA) on microglial activation and neuronal integrity, and to evaluate the influence of LTA exposure on sensitivity to the inflammation and neuronal dysfunction associated with Aβ. Using BV2 and N2a cells as an in vitro model, we highlight that acute exposure to LTA robustly promotes inflammatory cytokine and nitric oxide (NO) production in microglia but also in neurons, similar to that reported under longer-term and chronic inflammatory conditions. Moreover, we find that exposure to LTA can enhance sensitivity to subthreshold Aβ, promoting an ‘M1′-like phenotype in microglia and provoking dysregulation of neuronal activity in acute hippocampal slices. Anti-inflammatory agents, including mimetics of brain-derived neurotrophic factor (BDNF), have proven effective at alleviating chronic neuroinflammatory complications. We further examined the effects of 7,8,3-trihydroxyflavone (7,8,3-THF), a small-molecule TrkB agonist, on LTA-induced microglial activation. We report that 7,8,3-THF can significantly ameliorate interleukin (IL)-6 and NO production in LTA-stimulated BV2 cells. Taken together, our findings offer support for exploration of TLR2 as a potential target for therapeutic intervention into acute neuroinflammatory conditions. Moreover we propose that exposure to gram-positive bacterial pathogens may promote sensitivity to the inflammatory changes characteristic of the aged brain.

Toll样受体2（TLR2）是病原体（包括那些来自革兰氏阳性细菌的病原体）的主要传感器。它还可以介导内源性炎症信号（例如β-淀粉样肽（Aβ））的作用，从而促进小胶质细胞活化和随后的神经元功能异常，这是慢性神经炎性疾病的特征。最近，已经提出了TLR2在与急性炎症有关的疾病的发病机理中的作用，所述疾病包括焦虑症和抑郁症。当前的研究旨在表征TLR2激动剂脂磷壁酸（LTA）对小胶质细胞活化和神经元完整性的急性影响，并评估LTA暴露对对Aβ相关的炎症和神经元功能障碍的敏感性的影响。使用BV2和N2a细胞作为体外在模型中，我们强调指出，长期暴露于LTA会强烈促进小胶质细胞以及神经元中炎症细胞因子和一氧化氮（NO）的产生，这与长期和慢性炎症条件下的报道相似。此外，我们发现暴露于LTA可以增强对亚阈值Aβ的敏感性，在小胶质细胞中促进'M1'样表型，并引起急性海马切片神经元活动失调。包括脑源性神经营养因子（BDNF）模拟物在内的抗炎药已被证明可有效缓解慢性神经炎并发症。我们进一步检查了7,8,3-三羟基黄酮（7,8,3-THF），一种小分子TrkB激动剂，对LTA诱导的小胶质细胞活化的影响。我们报告说7,8，3-THF可以显着改善LTA刺激的BV2细胞中白介素（IL）-6和NO的产生。综上，我们的发现为TLR2的探索提供了支持，TLR2是治疗急性神经炎性疾病的潜在靶点。此外，我们建议暴露于革兰氏阳性细菌病原体可能会提高对衰老大脑特征性炎症变化的敏感性。