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.

中文翻译：

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小胶质细胞对外周 1 型干扰素的反应


干扰素 α (IFNα) 是一种细胞因子，其产生会因病毒感染和系统性红斑狼疮 (SLE) 等自身免疫性疾病而内源性增加。 IFNα 特征升高与临床观察到的神经行为缺陷有关，例如这些疾病中的轻度认知障碍、疲劳、抑郁和精神病。然而，这些神经精神症状背后的机制仍然很大程度上未知，并且尚不清楚 IFNα 信号如何影响中枢神经系统 (CNS) 功能。最近，异常的小胶质细胞介导的突触修剪和功能与多种神经退行性和神经精神疾病有关，但 IFNα 是否以及如何调节这些功能尚不清楚。使用外周 IFNα 给药模型，我们研究了小胶质细胞中 IFNAR 信号传导引起的基因表达变化。对野生型和小胶质细胞特异性 Ifnar1 条件敲除小鼠的分选小胶质细胞进行批量 RNA 测序，以评估 IFNα 和 IFNAR 信号依赖的基因表达变化。此外，通过免疫组织化学和流式细胞术评估了 IFNα 对小胶质细胞形态和突触吞噬的影响。我们发现，通过外周暴露的 IFNα 会在小胶质细胞中诱导独特的基因特征，其中包括预期的多个干扰素刺激基因 (ISG) 以及补体成分 C4b 的上调。我们还描述了小胶质细胞表型中一些 IFNα 依赖性变化，包括 CD45 和 CD68 的表达、细胞形态和突触前吞噬，这些变化揭示了大脑区域特异性的微妙差异。 最后，通过特异性敲低小胶质细胞上 IFNAR1 的表达，我们表明这些变化很大程度上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 信号转导的其他中枢神经系统实质细胞类型的间接信号传导作用。外周 IFNα 会诱导小胶质细胞发生独特的遗传和表型变化，这些变化很大程度上依赖于小胶质细胞 IFNAR 的直接信号传导。 IFNα 诱导的 C4b 上调可能在神经精神疾病的异常突触修剪中发挥重要作用。