Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.
Astellas Pharma Inc., Drug Discovery Research, Tsukuba, Japan.
Brain Behav Immun. 2020 Aug;88:826-839. doi: 10.1016/j.bbi.2020.05.055. Epub 2020 May 22.
The transcription factor nuclear factor kappa B (NF-κB) regulates the expression of many inflammatory genes that are overexpressed in a subset of people with schizophrenia. Transcriptional reduction in one NF-κB inhibitor, Human Immunodeficiency Virus Enhancer Binding Protein 2 (HIVEP2), is found in the brain of patients, aligning with evidence of NF-κB over-activity. Cellular co-expression of HIVEP2 and cytokine transcripts is a prerequisite for a direct effect of HIVEP2 on pro-inflammatory transcription, and we do not know if changes in HIVEP2 and markers of neuroinflammation are occurring in the same brain cell type. We performed in situ hybridisation on postmortem dorsolateral prefrontal cortex tissue to map and compare the expression of HIVEP2 and Serpin Family A Member 3 (SERPINA3), one of the most consistently increased inflammatory genes in schizophrenia, between schizophrenia patients and controls. We find that HIVEP2 expression is neuronal and is decreased in almost all grey matter cortical layers in schizophrenia patients with neuroinflammation, and that SERPINA3 is increased in the dorsolateral prefrontal cortex grey matter and white matter in the same group of patients. We are the first to map the upregulation of SERPINA3 to astrocytes and to some neurons, and find evidence to suggest that blood vessel-associated astrocytes are the main cellular source of SERPINA3 in the schizophrenia cortex. We show that a lack of HIVEP2 in mice does not cause astrocytic upregulation of Serpina3n but does induce its transcription in neurons. We speculate that HIVEP2 downregulation is not a direct cause of astrocytic pro-inflammatory cytokine synthesis in schizophrenia but may contribute to neuronally-mediated neuroinflammation.
转录因子核因子 kappa B（NF-κB）调节许多炎症基因的表达，这些基因在一部分精神分裂症患者中过度表达。在患者的大脑中发现一种 NF-κB 抑制剂人类免疫缺陷病毒增强子结合蛋白 2（HIVEP2）的转录减少，这与 NF-κB 过度活跃的证据一致。HIVEP2 和细胞因子转录物的细胞共表达是 HIVEP2 对促炎转录产生直接影响的前提，我们不知道 HIVEP2 和神经炎症标志物的变化是否发生在同一脑细胞类型中。我们对死后背外侧前额叶皮层组织进行原位杂交，以在精神分裂症患者和对照组之间绘制和比较 HIVEP2 和 Serpin 家族 A 成员 3（SERPINA3）的表达，SERPINA3 是精神分裂症中最一致增加的炎症基因之一。我们发现 HIVEP2 表达是神经元的，并且在有神经炎症的精神分裂症患者的几乎所有灰质皮层层中都减少，而 SERPINA3 在同一组患者的背外侧前额叶皮层灰质和白质中增加。我们是第一个将 SERPINA3 的上调映射到星形胶质细胞和一些神经元的人，并发现有证据表明，血管相关星形胶质细胞是精神分裂症皮层中 SERPINA3 的主要细胞来源。我们表明，缺乏 HIVEP2 在小鼠中不会引起星形胶质细胞中 Serpina3n 的上调，但会诱导其在神经元中的转录。我们推测，HIVEP2 的下调不是星形胶质细胞促炎细胞因子合成的直接原因，但可能有助于神经元介导的神经炎症。
