Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Ave, Chicago, IL 60611, USA.
J Neuroinflammation. 2012 Sep 17;9:217. doi: 10.1186/1742-2094-9-217.
Theiler's virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS). IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE) and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease.
Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO) were infected with Theiler's murine encephalomyelitis virus (1 x 106 PFU). Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry.
Administration of IL-1β, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6) mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence.
These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of inhibitory cytokines and regulatory molecules. Therefore, the balance of IL-1 signaling appears to be extremely important for the protection from TMEV-induced demyelinating disease, and either too much or too little signaling promotes the development of disease.
西尼罗河病毒感染可诱导小鼠发生慢性脱髓鞘疾病，已被作为多发性硬化症（MS）的传染性模型进行研究。IL-1 在自身免疫性疾病模型（EAE）和这种用于 MS 的病毒模型的发病机制中均发挥重要作用。然而，已知 IL-1 可发挥针对某些病毒感染的重要保护作用。因此，IL-1 介导的信号转导在 TMEV 诱导的脱髓鞘疾病发展中是发挥保护作用还是致病作用尚不清楚。
雌性 C57BL/6 小鼠和 B6.129S7-Il1r1tm1Imx/J 小鼠（IL-1R KO）感染西尼罗河病毒（1 x 106 PFU）。比较脱髓鞘疾病发展情况和组织病理学变化的差异。通过定量 PCR、ELISA 和流式细胞术分析感染小鼠的病毒持续存在、细胞因子产生和中枢神经系统免疫反应。
给予 IL-1β 使易患 TMEV 诱导的脱髓鞘疾病的抗性 B6 小鼠变得易感，导致高水平 Th17 反应。有趣的是，将 TMEV 感染入抗性 C57BL/6（B6）小鼠的 IL-1R 缺陷小鼠也可诱导 TMEV 诱导的脱髓鞘疾病。在 IL-1R 缺陷小鼠的病毒感染晚期发现高病毒持续存在，但在 WT B6 和 IL-1R 缺陷型小鼠之间，初始抗病毒免疫反应和病毒持续存在水平几乎没有差异。在 TMEV 感染的 IL-1R 缺陷型小鼠的中枢神经系统中，初始 I 型 IFN 反应和 PDL-1 和 Tim-3 的表达更高，导致 T 细胞功能缺陷，从而允许病毒持续存在。
这些结果表明，高水平 IL-1 的存在通过升高致病性 Th17 反应发挥致病作用，而缺乏 IL-1 信号则通过升高抑制性细胞因子和调节分子的产生促进脊髓中 T 细胞的激活，从而促进病毒持续存在，从而促进疾病发展。因此，IL-1 信号转导的平衡对于保护免受 TMEV 诱导的脱髓鞘疾病非常重要，过多或过少的信号均会促进疾病的发展。
