NORMENT, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT, Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen-Thrombosis Research and Expertise Center (TREC), University of Tromsø, Tromsø, Norway.
Brain Behav Immun. 2020 Jul;87:634-644. doi: 10.1016/j.bbi.2020.02.008. Epub 2020 Feb 25.
Schizophrenia (SCZ) is a severe mental disorder with a high heritability. Although its pathophysiology is mainly unknown, dysregulated immune activation and inflammation have recently emerged as possible candidates in the underlying mechanisms of SCZ. Previous studies suggest that aberrant inflammasome activation, glia dysregulation, and brain inflammation may be involved in the pathophysiology of the disorder. Here, we studied the effects of inflammatory modulation on human induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Inflammasome activation was mimicked by short-term IL-1β exposure, and gene expression were measured with high-coverage RNA-Seq to ensure a global characterization of the transcriptional effects of the treatment. IL-1β exposure modulated several pathways involved in innate immune responses, cell cycle regulation, and metabolism in both SCZ and CTRL astrocytes. Significant differences were found in the expression of HILPDA and CCL20 genes, both of which had reduced up-regulation upon IL-1β treatment in SCZ astrocytes compared to CTRL astrocytes. CCL20 data were further validated and confirmed using qPCR, ELISA, and regulatory T lymphocyte (T) migration assays. Additionally, we found significantly decreased mRNA expression of the T-specific marker FOXP3 in the blood of a large cohort of SCZ patients (n = 484) compared to CTRL (n = 472). Since CCL20 is a specific chemoattractant for CD4CD25CCR6 T, which are crucially involved in anti-inflammatory responses during brain (auto)inflammation, our results imply a plausible role for an altered astroglia-CCL20-CCR6-T axis in SCZ pathophysiology.
精神分裂症 (SCZ) 是一种具有高遗传性的严重精神障碍。尽管其病理生理学主要未知，但最近免疫激活和炎症失调已成为 SCZ 潜在机制的候选者。先前的研究表明，异常的炎性小体激活、神经胶质失调和脑炎症可能与该疾病的病理生理学有关。在这里，我们研究了炎症调节对源自 SCZ 患者和健康对照者 (CTRL) 的人诱导多能干细胞 (iPSC) 衍生星形胶质细胞的影响。通过短期 IL-1β 暴露模拟炎性小体激活，并使用高覆盖率 RNA-Seq 测量基因表达，以确保对处理的转录效应进行全面表征。IL-1β 暴露调节了参与先天免疫反应、细胞周期调节和代谢的几个途径，在 SCZ 和 CTRL 星形胶质细胞中均有作用。在 HILPDA 和 CCL20 基因的表达中发现了显著差异，与 CTRL 星形胶质细胞相比，IL-1β 处理后 SCZ 星形胶质细胞中这两种基因的上调均减少。使用 qPCR、ELISA 和调节性 T 淋巴细胞 (T) 迁移测定进一步验证和确认了 CCL20 数据。此外，我们发现与 CTRL 相比，大量 SCZ 患者 (n=484) 的血液中 T 特异性标记物 FOXP3 的 mRNA 表达显著降低。由于 CCL20 是 CD4CD25CCR6 T 的特异性趋化因子，而 CD4CD25CCR6 T 在脑 (自身) 炎症期间的抗炎反应中至关重要，因此我们的结果暗示了星形胶质细胞-CCL20-CCR6-T 轴的改变在 SCZ 病理生理学中的可能作用。
