Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation.
Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation.
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DOI：
10.1038/s41380-018-0235-x
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发表时间：
2020-04
影响因子：
11
通讯作者：
Weickert CS
中科院分区：
文献类型：
--
作者：
Cai HQ;Catts VS;Webster MJ;Galletly C;Liu D;O'Donnell M;Weickert TW;Weickert CS
精神分裂症患者的血液和大脑中都存在升高的促炎细胞因子，但这如何影响血脑屏障（BBB）的分子指标尚不清楚。通过qPCR测量了37名精神分裂症/情感性精神障碍患者和37名匹配对照者的前额叶皮层中与BBB功能相关的8种mRNA、小胶质细胞和3种免疫细胞标志物。该队列先前基于皮质炎症相关转录物被分组为“高炎症”和“低炎症”亚组。测定了78例精神分裂症/情感性精神障碍患者和73例健康对照者血浆可溶性细胞间粘附分子1（sICAM 1）。我们发现sICAM 1在精神分裂症中显著升高。外排转运蛋白ABCG 2在精神分裂症脑中较低，而编码VE-钙粘蛋白和ICAM 1的mRNA则较高。与“低炎症”精神分裂症和“低炎症”对照亚组相比，“高炎症”精神分裂症亚组具有较低的ABCG 2和较高的ICAM 1、VE-钙粘蛋白、闭合蛋白和干扰素诱导的跨膜蛋白mRNA。ICAM 1免疫组化显示富集在脑内皮细胞，无论诊断和局部星形胶质细胞在一些大脑。小胶质细胞mRNA在精神分裂症中没有改变，也没有与ICAM 1表达相关。与“低炎症”精神分裂症和对照组相比，“高炎症”精神分裂症中的免疫细胞mRNA升高。在40%以上的“高度炎症”精神分裂症脑组织中，通过免疫组化在脑实质中鉴定出CD 163+血管周围巨噬细胞。高水平细胞因子表达和精神分裂症的人显示出与通过增加ICAM 1进入大脑的更大免疫细胞迁移一致的变化，这可能有助于在该亚组人群中发现的其他神经病理学变化。
Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood–brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into “high inflammation” and “low inflammation” subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The “high inflammation” schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both “low inflammation” schizophrenia and “low inflammation” control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in “high inflammation” schizophrenia compared to both “low inflammation” schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of “high inflammation” schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.
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