Barichello Tatiana, Simoes Lutiana R, Quevedo Joao, Zhang Xiang Y
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
Experimental Pathophysiology Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
Curr Top Behav Neurosci. 2020;44:161-205. doi: 10.1007/7854_2018_81.
Clinical and pre-clinical studies have demonstrated an important role of neuroinflammation in the etiology of schizophrenia. While the underlying mechanisms remain poorly understood, there are some studies demonstrating an association between maternal immune activation and behavioral changes in adult offspring and identifying early life infection as a trigger for schizophrenia; in addition, inflammatory markers were found to be increased in the schizophrenic post-mortem brain. During maternal immune activation, pro-inflammatory mediators such as cytokines, chemokines, antibodies, and acute-phase proteins are released in the maternal bloodstream, thus increasing the permeability of the placental barrier and the fetal blood-brain barrier, allowing the inflammatory mediators to enter the fetal brain. In the central nervous system (CNS), these pro-inflammatory mediators are able to activate microglial cells that can release pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6. As a consequence, circulating immune cells may infiltrate the brain, increasing cytokine levels and releasing antibodies that aggravate the neuroinflammation. Neuroinflammation may affect processes that are pivotal for normal brain maturation such as myelination, synaptic pruning, and neuronal remodeling. Microglial cell activation and pro-inflammatory mediators have been extensively studied in schizophrenic post-mortem brain samples. Some results of these investigations demonstrated an increase in microglial activation markers, cytokines, and chemokines in post-mortem brain samples from individuals with schizophrenia. In contrast, there are studies that have demonstrated low levels of microglial activation makers in the schizophrenic post-mortem brain. Thus, based on the important role of neuroinflammation as a trigger in the development of schizophrenia, this chapter aims (1) to enumerate evidence of neuroinflammation and microglial activation from pre-clinical schizophrenia models, (2) to show links between schizophrenia and neuroinflammation in clinical studies, and (3) to identify mechanisms by which microglial activation may influence in the development of schizophrenia.
临床和临床前研究已证明神经炎症在精神分裂症病因学中起重要作用。尽管其潜在机制仍知之甚少，但有一些研究表明母体免疫激活与成年后代的行为变化之间存在关联，并将早期感染确定为精神分裂症的触发因素；此外，在精神分裂症患者的尸检大脑中发现炎症标志物增加。在母体免疫激活期间，促炎介质如细胞因子、趋化因子、抗体和急性期蛋白会释放到母体血液中，从而增加胎盘屏障和胎儿血脑屏障的通透性，使炎症介质进入胎儿大脑。在中枢神经系统（CNS）中，这些促炎介质能够激活小胶质细胞，小胶质细胞可释放促炎细胞因子，如肿瘤坏死因子α（TNF-α）、白细胞介素（IL）-1β和IL-6。结果，循环免疫细胞可能浸润大脑，增加细胞因子水平并释放加重神经炎症的抗体。神经炎症可能影响正常大脑成熟的关键过程，如髓鞘形成、突触修剪和神经元重塑。小胶质细胞激活和促炎介质已在精神分裂症患者的尸检脑样本中得到广泛研究。这些研究的一些结果表明，精神分裂症患者尸检脑样本中的小胶质细胞激活标志物、细胞因子和趋化因子增加。相比之下，有研究表明精神分裂症患者尸检大脑中的小胶质细胞激活标志物水平较低。因此，基于神经炎症作为精神分裂症发展触发因素的重要作用，本章旨在（1）列举临床前精神分裂症模型中神经炎症和小胶质细胞激活的证据，（2）展示临床研究中精神分裂症与神经炎症之间的联系，以及（3）确定小胶质细胞激活可能影响精神分裂症发展的机制。
