Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis.
Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis.
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DOI：
10.1186/s12974-016-0757-6
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发表时间：
2016-11-15
影响因子：
9.3
通讯作者：
Calzà L
中科院分区：
文献类型：
--
作者：
Borjini N;Fernández M;Giardino L;Calzà L
实验性变态反应性脑脊髓炎（EAE）是人类多发性硬化症（MS）最常用的实验动物模型，迄今为止已用于研究疾病的急性和缓解-复发阶段。尽管有大量关于EAE神经炎症发作和进展的文献，但重要的问题仍然是开放的，特别是关于免疫和临床发作之间的早期无症状阶段。在这项研究中，我们进行了一个时间过程的研究神经炎症和脱髓鞘生物标志物在脊髓（SC），脑脊液（CSF），和血液中诱导的EAE在黑暗agglomerate（DA）雌性大鼠相比，对照组和促凝剂注射大鼠，使用高通量技术的基因表达和蛋白质测定，并侧重于免疫，临床发作之间的时间过程，（免疫后1、5、8天（DPI））和进展（11和18 DPI）。在组织中分析了与T细胞活化/信号传导、适应性免疫、细胞因子/趋化因子炎症、脱髓鞘和细胞应激相关的84种基因的表达谱;在CSF和血浆中测量了24种细胞因子。巨噬细胞集落刺激因子（CSF 1）是第一个上调的蛋白，远至1 DPI，不仅在血液中，而且在CSF和SC中。GW 2580，一种选择性CSF 1 R抑制剂，治疗减缓了疾病的进展，显着降低了严重程度，并防止复发阶段。此外，促炎细胞因子（IL-1β、TNF-α）和抗炎细胞因子（IL-5、IL-10、VEGF）从8 DPI开始上调。髓鞘基因从8 DPI开始下调，尤其是MAL、MBP和PMP 22，而炎症相关基因如CXCL 11和CXCL 10则观察到相反的表达谱。这种早期细胞因子和趋化因子的调节表明，新的生物标志物和治疗选择可以在EAE的无症状阶段进行探索。总的来说，我们的研究结果提供了明确的证据表明，CSF 1 R信号调节EAE中的炎症，支持MS中CSF 1 R的治疗靶向。
Experimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset. In this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI). The expression profile of 84 genes related to T cell activation/signaling, adaptive immunity, cytokine/chemokine inflammation, demyelination, and cellular stress were analyzed in the tissue; 24 cytokines were measured in the CSF and plasma. The macrophage colony-stimulating factor (CSF1) was the first up-regulated protein as far as 1 DPI, not only in blood but also in CSF and SC. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity, and prevented the relapse phase. Moreover, both pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory cytokines (IL-5, IL-10, VEGF) were up-regulated starting from 8 DPI. Myelin genes were down-regulated starting from 8 DPI, especially MAL, MBP, and PMP22 while an opposite expression profile was observed for inflammation-related genes, such as CXCL11 and CXCL10. This early cytokine and chemokine regulation indicates that novel biomarkers and therapeutic options could be explored in the asymptomatic phase of EAE. Overall, our findings provide clear evidence that CSF1R signaling regulates inflammation in EAE, supporting therapeutic targeting of CSF1R in MS.
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通讯作者：
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5.3
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