Microglial responses to peripheral type 1 interferon.
Microglial responses to peripheral type 1 interferon.
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DOI：
10.1186/s12974-020-02003-z
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发表时间：
2020-11-12
影响因子：
9.3
通讯作者：
Carroll M
中科院分区：
文献类型：
--
作者：
Aw E;Zhang Y;Carroll M
干扰素α（IFNα）是一种细胞因子，其产生在响应病毒感染和自身免疫性疾病如系统性红斑狼疮（SLE）时内源性增加。在这些疾病中，IFNα信号升高与临床观察到的神经行为缺陷相关，如轻度认知障碍、疲劳、抑郁和精神病。然而，这些神经精神症状的潜在机制在很大程度上仍不清楚，目前还不清楚IFNα信号传导如何影响中枢神经系统（CNS）功能。异常的小胶质细胞介导的突触修剪和功能最近被牵连在一些神经退行性和神经精神疾病，但是否以及如何IFNα调节这些功能还没有很好的定义。使用外周IFNα给药模型，我们研究了小胶质细胞中IFNAR信号转导引起的基因表达变化。对来自野生型和小胶质细胞特异性Ifnar 1条件性敲除小鼠的分选小胶质细胞进行批量RNA测序，以评价基因表达中IFNα和IFNAR信号传导依赖性变化。通过免疫组化和流式细胞术检测IFNα对小胶质细胞形态和突触吞噬的影响。我们发现，通过外周暴露IFNα诱导小胶质细胞中的独特基因特征，包括预期的多个干扰素刺激基因（ISG）以及补体成分C4 b的上调。我们还描述了小胶质细胞表型的几种IFNα依赖性变化，包括CD 45和CD 68的表达、细胞形态和突触前吞噬，这些变化揭示了细微的脑区域特异性差异。最后，通过特异性地敲低小胶质细胞上IFNAR 1的表达，我们表明这些变化主要归因于小胶质细胞上的直接IFNAR信号传导，而不是来自能够进行IFNα-IFNAR信号转导的其他CNS实质细胞类型的间接信号传导效应。外周IFNα诱导小胶质细胞中独特的遗传和表型变化，这些变化在很大程度上依赖于通过小胶质细胞IFNAR的直接信号传导。IFNα诱导的C4 b上调可能在神经精神疾病的异常突触修剪中起重要作用。补充信息随附于10.1186/s12974-020-02003-z。
Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFNα modulates these functions are not well defined. Using a model of peripheral IFNα administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFNα and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFNα on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. We found that IFNα exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFNα-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region-specific differences. Finally, by specifically knocking down expression of IFNAR1 on microglia, we show that these changes are largely attributable to direct IFNAR signalling on microglia and not from indirect signalling effects through other CNS parenchymal cell types which are capable of IFNα-IFNAR signal transduction. Peripheral IFNα induces unique genetic and phenotypic changes in microglia that are largely dependent on direct signalling through microglial IFNAR. The IFNα-induced upregulation of C4b could play important roles in the context of aberrant synaptic pruning in neuropsychiatric disease. Supplementary information accompanies this paper at 10.1186/s12974-020-02003-z.
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影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
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影响因子：
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作者：
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通讯作者：
Fujinami, Robert S.
影响因子：
11
作者：
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