Over-activation of the innate immune system constitutes a risk factor for the development of nervous system disorders but may reduce the severity of these disorders by inducing tolerance effect. Here, we studied the tolerance-inducing effect and properties of innate immune stimulation on chronic social defeat stress (CSDS)-induced behavioral abnormalities in mice. A single injection of the innate immune enhancer lipopolysaccharide (LPS) one day before stress exposure prevented CSDS-induced impairment in social interaction and increased immobility time in the tail suspension test and forced swimming test. This effect was observed at varying doses (100, 500, and 1000 μg/kg) and peaked at 100 μg/kg. A single LPS injection (100 μg/kg) either one or five but not ten days before stress exposure prevented CSDS-induced behavioral abnormalities. A second LPS injection ten days after the first LPS injection, or a 2× or 4× LPS injections ten days before stress exposure also induced tolerance against stress-induced behavioral abnormalities. Our results furthermore showed that a single LPS injection one day before stress exposure skewed the neuroinflammatory response in the hippocampus and prefrontal cortex of CSDS-exposed mice toward an anti-inflammatory phenotype. Inhibiting the central innate immune response by pretreatment with minocycline or PLX3397 abrogated the tolerance-inducing effect of LPS preconditioning on CSDS-induced behavioral abnormalities and neuroinflammatory responses in the brain. These results provide evidence for a prophylactic effect of innate immune stimulation on stress-induced behavioral abnormalities via changes in microglial activation, which may help develop novel strategies for the prevention of stress-induced psychological disorders.

中文翻译：

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先天免疫刺激对小鼠慢性应激行为异常的耐受诱导作用及特性

先天免疫系统的过度激活构成了神经系统疾病发展的危险因素，但可以通过诱导耐受效应来降低这些疾病的严重程度。在这里，我们研究了先天免疫刺激对慢性社交失败压力 (CSDS) 诱导的小鼠行为异常的耐受诱导作用和特性。在压力暴露前一天单次注射先天免疫增强剂脂多糖 (LPS) 可防止 CSDS 引起的社会交往障碍，并增加悬尾试验和强迫游泳试验中的不动时间。这种效应在不同剂量（100、500 和 1000 μg/kg）下观察到，并在 100 μg/kg 时达到峰值。在压力暴露前 1 天或 5 天但不是 10 天，单次注射 LPS（100 μg/kg）可防止 CSDS 引起的行为异常。第一次 LPS 注射十天后的第二次 LPS 注射，或压力暴露前十天的 2 倍或 4 倍 LPS 注射也诱导了对压力引起的行为异常的耐受性。我们的结果进一步表明，在压力暴露前一天注射一次 LPS 会使 CSDS 暴露小鼠的海马和前额叶皮层的神经炎症反应偏向抗炎表型。通过用米诺环素或 PLX3397 预处理抑制中枢先天免疫反应消除了 LPS 预处理对 CSDS 诱导的大脑行为异常和神经炎症反应的耐受诱导作用。这些结果提供了先天免疫刺激通过小胶质细胞激活的变化对压力引起的行为异常的预防作用的证据，