Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
Department of Psychosomatic and Psychiatric Diseases, Huzhou Third Municipal Hospital Huzhou, the Affiliated Hospital of Huzhou University, #2088 Tiaoxi East Road, Huzhou 313000, Zhejiang, China.
Brain Behav Immun. 2021 Jan;91:451-471. doi: 10.1016/j.bbi.2020.11.002. Epub 2020 Nov 4.
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.
先天免疫系统的过度激活是神经系统疾病发展的一个风险因素，但它可能通过诱导耐受效应来减轻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会挫败应激（CSDS）诱导的小鼠行为异常的诱导耐受效应和特性。应激暴露前一天单次注射先天免疫增强剂脂多糖（LPS）可预防 CSDS 引起的社交互动障碍，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 1000μg/kg）下观察到，在 100μg/kg 时达到峰值。应激暴露前一天单次注射 LPS（100μg/kg）一次、五次或十次均可预防 CSDS 引起的行为异常。应激暴露前十天内单次 LPS 注射（100μg/kg）一次或五次但不是十次也可预防 CSDS 引起的行为异常。应激暴露前十天内两次 LPS 注射或四次 LPS 注射也可诱导对应激诱导的行为异常的耐受。我们的结果还表明，应激暴露前一天单次 LPS 注射使 CSDS 暴露小鼠海马体和前额叶皮质中的神经炎症反应向抗炎表型倾斜。预先用米诺环素或 PLX3397 抑制中枢先天免疫反应会消除 LPS 预处理对 CSDS 诱导的行为异常和大脑神经炎症反应的诱导耐受效应。这些结果为先天免疫刺激通过改变小胶质细胞激活对应激诱导的行为异常的预防作用提供了证据，这可能有助于开发预防应激诱导的心理障碍的新策略。
