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重度抑郁症中小胶质细胞的转录组图谱分析显示皮质灰色物质中小胶质细胞的抑制。

Microglia Transcriptional Profiling in Major Depressive Disorder Shows Inhibition of Cortical Gray Matter Microglia.

机构信息

Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands; Psychiatric Program of the Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands; Department of Psychiatry, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, the Netherlands.

出版信息

Biol Psychiatry. 2023 Oct 15;94(8):619-629. doi: 10.1016/j.biopsych.2023.04.020. Epub 2023 Apr 28.

DOI:10.1016/j.biopsych.2023.04.020

PMID:37121366

Abstract

BACKGROUND

Microglia have been implicated in the pathophysiology of major depressive disorder (MDD), but information on biological mechanisms is limited. Therefore, we investigated the gene expression profile of microglial cells in relation to neuronal regulators of microglia activity in well-characterized MDD and control autopsy brains.

METHODS

Pure, intact microglia were isolated at brain autopsy from occipital cortex gray matter (GM) and corpus callosum white matter of 13 donors with MDD and 10 age-matched control donors for RNA sequencing. Top differentially expressed genes were validated using immunohistochemistry staining. Because gene expression changes were only detected in GM microglia, neuronal regulators of microglia were investigated in cortical tissue and synaptosomes from the cortex by reverse transcriptase-quantitative polymerase chain reaction and Western blot.

RESULTS

Transcriptome analysis revealed 92 genes differentially expressed in microglia isolated from GM, but none in microglia from white matter in donors with MDD, compared with control donors. Of these, 81 genes were less abundantly expressed in GM in MDD, including CD163, MKI67, SPP1, CD14, FCGR1A/C, and C1QA/B/C. Accordingly, pathways related to effector mechanisms, such as the complement system and phagocytosis, were differentially regulated in GM microglia in MDD. Immunohistochemistry staining revealed significantly lower expression of CD163 protein in MDD. Whole tissue analysis showed an increase in CD200 (p = .0009) and CD47 (p = .068) messenger RNA, and CD47 protein was significantly elevated (p = .0396) in synaptic fractions of MDD cases.

CONCLUSIONS

Transcriptional profiling indicates an immune-suppressed microglial phenotype in MDD that is possibly caused by neuronal regulation.

摘要

背景

小胶质细胞被认为与重度抑郁症（MDD）的病理生理学有关，但有关生物学机制的信息有限。因此，我们研究了在特征明确的 MDD 和对照尸检大脑中，与神经元调节小胶质细胞活性相关的小胶质细胞的基因表达谱。

方法

从 13 名 MDD 患者和 10 名年龄匹配的对照尸检患者的枕叶皮质灰质（GM）和胼胝体白质中，在尸检时分离出纯、完整的小胶质细胞，进行 RNA 测序。使用免疫组织化学染色验证差异表达的基因。由于仅在 GM 小胶质细胞中检测到基因表达变化，因此通过逆转录定量聚合酶链反应和 Western blot 研究了皮质组织和皮质突触体中小胶质细胞的神经元调节剂。

结果

转录组分析显示，与对照供体相比，MDD 供体 GM 中分离的小胶质细胞中有 92 个基因差异表达，但在白质中没有。其中，81 个基因在 MDD 的 GM 中表达水平较低，包括 CD163、MKI67、SPP1、CD14、FCGR1A/C 和 C1QA/B/C。相应地，补体系统和吞噬作用等效应机制相关的途径在 MDD 的 GM 小胶质细胞中受到差异调节。免疫组织化学染色显示 CD163 蛋白在 MDD 中表达明显降低。全组织分析显示 MDD 病例中 CD200（p=0.0009）和 CD47（p=0.068）信使 RNA 增加，突触分数中 CD47 蛋白明显升高（p=0.0396）。