Tribouillard-Tanvier Déborah, Striebel James F, Peterson Karin E, Chesebro Bruce
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
J Virol. 2009 Nov;83(21):11244-53. doi: 10.1128/JVI.01413-09. Epub 2009 Aug 26.
Activation of microglia and astroglia is seen in many neurodegenerative diseases including prion diseases. Activated glial cells produce cytokines as a protective response against certain pathogens and as part of the host inflammatory response to brain damage. In addition, cytokines might also exacerbate tissue damage initiated by other processes. In the present work using multiplex assays to analyze protein levels of 24 cytokines in scrapie agent-infected C57BL/10 mouse brains, we observed elevation of CCL2, CCL5, CXCL1, CXCL10, granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma interferon (IFN-gamma), interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, and IL-12p40. Scrapie agent-infected wild-type mice and transgenic mice expressing anchorless prion protein (PrP) had similar cytokine responses in spite of extensive differences in neuropathology. Therefore, these responses may be primarily a reaction to brain damage induced by prion infection rather than specific inducers of a particular type of pathology. To study the roles of astroglia and microglia in these cytokine responses, primary glial cultures were exposed to scrapie agent-infected brain homogenates. Microglia produced only IL-12p40 and CXCL10, whereas astroglia produced these cytokines plus CCL2, CCL3, CCL5, CXCL1, G-CSF, IL-1beta, IL-6, IL-12p70, and IL-13. Glial cytokine responses from wild-type mice and transgenic mice expressing anchorless PrP differed only slightly, but glia from PrP-null mice produced only IL-12p40, indicating that PrP expression was required for scrapie agent induction of other cytokines detected. The difference in cytokine response between microglia and astroglia correlated with 20-fold-higher levels of PrP expression in astroglia versus microglia, suggesting that high-level PrP expression on astroglia might be important for induction of certain cytokines.
在包括朊病毒病在内的许多神经退行性疾病中都能看到小胶质细胞和星形胶质细胞的激活。活化的神经胶质细胞会产生细胞因子，作为对某些病原体的保护性反应以及宿主对脑损伤炎症反应的一部分。此外，细胞因子也可能会加剧由其他过程引发的组织损伤。在本研究中，我们使用多重检测法分析了羊瘙痒病病原体感染的C57BL/10小鼠大脑中24种细胞因子的蛋白质水平，观察到CCL2、CCL5、CXCL1、CXCL10、粒细胞-巨噬细胞集落刺激因子（GM-CSF）、γ干扰素（IFN-γ）、白细胞介素1α（IL-1α）、IL-1β、IL-6和IL-12p40水平升高。尽管神经病理学存在广泛差异，但羊瘙痒病病原体感染的野生型小鼠和表达无锚定朊病毒蛋白（PrP）的转基因小鼠具有相似的细胞因子反应。因此，这些反应可能主要是对朊病毒感染引起的脑损伤的反应，而不是特定类型病理学的特异性诱导剂。为了研究星形胶质细胞和小胶质细胞在这些细胞因子反应中的作用，将原代神经胶质细胞培养物暴露于羊瘙痒病病原体感染的脑匀浆中。小胶质细胞仅产生IL-12p40和CXCL10，而星形胶质细胞产生这些细胞因子以及CCL2、CCL3、CCL5、CXCL1、G-CSF、IL-1β、IL-6、IL-12p70和IL-13。野生型小鼠和表达无锚定PrP的转基因小鼠的神经胶质细胞因子反应仅略有不同，但PrP基因敲除小鼠的神经胶质细胞仅产生IL-12p40，这表明PrP表达是检测到的羊瘙痒病病原体诱导其他细胞因子所必需的。小胶质细胞和星形胶质细胞之间细胞因子反应的差异与星形胶质细胞中PrP表达水平比小胶质细胞高20倍相关，这表明星形胶质细胞上的高水平PrP表达可能对某些细胞因子的诱导很重要。
