Interferon downstream signaling is activated early in pre-symptomatic Niemann-Pick disease type C
Interferon downstream signaling is activated early in pre-symptomatic Niemann-Pick disease type C
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DOI：
10.1016/j.neulet.2019.05.005
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发表时间：
2019-07-27
影响因子：
2.5
通讯作者：
Soriano, Salvador
中科院分区：
文献类型：
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作者：
Shin, Samuel D.;Shin, Alexandra;Soriano, Salvador
C型尼曼-匹克病（NPC）是一种致命的神经退行性疾病，没有FDA批准的治疗方法。以往的研究表明，神经炎症是NPC的早期病理事件和疾病修饰因子，影响症状发作和总体寿命。因此，NPC特异性抗炎治疗可能会产生临床获益。然而，迄今为止，炎症发作的初始触发因素和驱动持续慢性神经炎症的机制仍然未知。在这项研究中，我们利用全基因组转录组分析，以确定参与早期鼻咽癌的关键途径。我们的研究结果表明，干扰素下游信号的非典型模式，涉及IFN-γ和IFN-α反应基因被激活的症状前Npc 1（-/-）小脑。差异表达基因的功能分析强调了小胶质细胞活化、抗病毒反应以及T淋巴细胞活化和趋化途径。多重蛋白质分析证实，一种有效的IFN-γ应答细胞因子IP-10/CXCL 10在症状前阶段显著上调，并在终末期进一步加重。此外，几种IFN-γ应答细胞因子在终末期Npc 1（-/-）小脑中升高，包括IFN-γ/CXCL 9、MCP-1/CCL 2、MIP-1 α/CCL 3、MIP-1 β/CCL 4、RANTES/CCL 5、M-CSF和IL-1 α。总之，我们的研究结果描述了一种新的激活模式的干扰素下游信号在症状前的NPC，以及关键的炎症介质，可以作为潜在的目标NPC特异性抗炎治疗。
Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition with no FDA-approved therapy. Previous studies demonstrated that neuroinflammation is an early pathologic event and a disease modifier of NPC, affecting symptomatic onset and overall lifespan. Therefore, NPC-specific anti-inflammatory therapy may result in clinical benefit. However, to date, the initial trigger of the inflammatory onset and the mechanism driving the sustained chronic neuroinflammation remain unknown. In this study, we utilized a genome-wide transcriptome analysis to identify the key pathways involved in early NPC. Our results showed that an atypical pattern of interferon downstream signaling that involves both IFN-gamma- and IFN-alpha-responsive genes is activated in pre-symptomatic Npc1(-/-) cerebella. Functional analysis of the differentially expressed genes highlighted microglial activation, anti-viral response, and T-lymphocyte activation and chemotaxis pathways. Multiplex protein analysis confirmed that a potent IFN-gamma-responsive cytokine, IP-10/CXCL10 was significantly upregulated in the pre-symptomatic stage and further exacerbated in the terminal stage. In addition, several IFN-gamma-responsive cytokines were elevated in the terminal stage Npc1(-/-) cerebella, including MIG/CXCL9, MCP-1/CCL2, MIP-1 alpha/CCL3, MIP-1 beta/CCL4, RANTES/CCL5, M-CSF, and IL-1 alpha. Together, our results describe a novel activation pattern of interferon downstream signaling in pre-symptomatic NPC, as well as key inflammatory mediators that could serve as potential targets for NPC-specific anti-inflammatory therapy.