Corsi-Zuelli Fabiana, Fachim Helene Aparecida, Loureiro Camila Marcelino, Shuhama Rosana, Bertozi Giuliana, Joca Sâmia Regiane Lourenço, Menezes Paulo Rossi, Louzada-Junior Paulo, Del-Ben Cristina Marta
Division of Psychiatry, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, United Kingdom.
Front Neurosci. 2019 Jan 11;12:1011. doi: 10.3389/fnins.2018.01011. eCollection 2018.
Life stressors during critical periods are reported to trigger an immune dysfunction characterised by abnormal production of inflammatory cytokines. Despite the relationship between early stressors and schizophrenia is described, the evidence on inflammatory biomarkers remains limited. We aimed to investigate whether an imbalance between pro- and anti-inflammatory cytokines in the brain is reflected in the peripheral blood of rats submitted to post-weaning social isolation (pwSI), a model with validity to study schizophrenia. We evaluated pro- and anti-inflammatory cytokines (IL-6, TNF-α, and IL-10) simultaneously at blood, prefrontal cortex and hippocampal tissues (Milliplex MAP), including the respective cytokines gene expression (mRNA) (qRT-PCR TaqMan mastermix). We also performed a correlation matrix to explore significant correlations among cytokines (protein and mRNA) in blood and brain, as well as cytokines and total number of square crossings in the open field for isolated-reared animals. Male rats ( = 10/group) were kept isolated ( = 1/cage) or grouped ( = 3-4/cage) since weaning for 10 weeks. After this period, rats were assessed for locomotion and sacrificed for blood and brain cytokines measurements. Prolonged pwSI decreased IL-10 protein and mRNA in the blood, and IL-10 protein in the hippocampus, along with decreased IL-6 and its mRNA expression in the prefrontal cortex. Our results also showed that cytokines tend to correlate to one-another among the compartments investigated, although blood and brain correlations are far from perfect. IL-10 hippocampal levels were negatively correlated with hyperlocomotion in the open field. Despite the unexpected decrease in IL-6 and unchanged TNF-α levels contrast to the expected pro-inflammatory phenotype, this may suggest that reduced anti-inflammatory signalling may be critical for eliciting abnormal behaviour in adulthood. Altogether, these results suggest that prolonged early-life adverse events reduce the ability to build proper anti-inflammatory cytokine that is translated from blood-to-brain.
据报道，关键时期的生活应激源会引发以炎性细胞因子产生异常为特征的免疫功能障碍。尽管早期应激源与精神分裂症之间的关系已有描述，但关于炎性生物标志物的证据仍然有限。我们旨在研究大脑中促炎和抗炎细胞因子之间的失衡是否反映在经历断奶后社会隔离（pwSI）的大鼠外周血中，pwSI是一种用于研究精神分裂症的有效模型。我们同时评估了血液、前额叶皮质和海马组织（Milliplex MAP）中的促炎和抗炎细胞因子（IL-6、TNF-α和IL-10），包括各自细胞因子的基因表达（mRNA）（qRT-PCR TaqMan预混液）。我们还进行了相关矩阵分析，以探索血液和大脑中细胞因子（蛋白质和mRNA）之间以及细胞因子与隔离饲养动物在旷场试验中的总穿越格数之间的显著相关性。雄性大鼠（每组 = 10只）自断奶后一直单独饲养（每笼 = 1只）或分组饲养（每笼 = 3 - 4只），持续10周。在此期间后，对大鼠的运动能力进行评估，并处死以测量血液和大脑中的细胞因子。长期的pwSI降低了血液中IL-10蛋白和mRNA以及海马中IL-10蛋白水平，同时降低了前额叶皮质中IL-6及其mRNA表达。我们的结果还表明，在所研究的各部分中细胞因子往往相互关联，尽管血液和大脑之间的相关性并不完美。海马中IL-10水平与旷场试验中的运动亢进呈负相关。尽管与预期的促炎表型相比，IL-6意外降低且TNF-α水平未变，但这可能表明抗炎信号传导减少可能对成年期异常行为的引发至关重要。总之，这些结果表明早期长期的不良事件会降低构建从血液到大脑的适当抗炎细胞因子的能力。
