Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
J Neuroinflammation. 2011 Dec 21;8:178. doi: 10.1186/1742-2094-8-178.
We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler's murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease.
SJL/J and B6;129S-Tlr3tm1Flv/J (TLR3KO-B6) mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler's murine encephalomyelitis virus (2 × 105 PFU) with or without treatment with 50 μg of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed.
We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4+ and CD8+ T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-γ-producing CD4+ and CD8+ T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-γ-producing CD4+ and CD8+ T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and regulatory FoxP3+ CD4+ T cells in the CNS, while poly IC-post-treated mice expressed reduced levels of PDL-1 and FoxP3+ CD4+ T cells.
These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction prior to viral infection leads to pathogenesis via over-activation of the pathogenic immune response.
我们之前已经表明，Toll 样受体 3（TLR3）介导的信号转导在诱导对 Theiler 鼠脑脊髓炎病毒（TMEV）感染的固有细胞因子反应中起重要作用。此外，与抗性 C57BL/6 小鼠相比，易感 SJL 小鼠的神经胶质细胞中 TMEV 感染后产生的细胞因子水平明显更高。然而，TLR3 介导的信号转导在脱髓鞘疾病的发展中是否发挥保护或致病作用尚不清楚。
用 Theiler 鼠脑脊髓炎病毒（2×105PFU）感染 SJL/J 和 B6；129S-Tlr3tm1Flv/J（TLR3KO-B6）小鼠以及将 TLR3KO-B6 小鼠回交 SJL/J 小鼠 6 代的 TLR3KO-SJL 小鼠，并用 50μg 的 poly IC 进行治疗或不进行治疗。分析感染小鼠中枢神经系统和外周血中细胞因子的产生和免疫反应。
我们研究了 TLR3 介导的信号转导在 TMEV 诱导的脱髓鞘疾病的保护和发病机制中的作用。尽管 TLR3KO-B6 小鼠的中枢神经系统中的病毒载量升高，但它们并未发展出脱髓鞘疾病。然而，与正常同窝小鼠相比，TLR3KO-SJL 小鼠的中枢神经系统中的病毒载量和细胞浸润增加，并且脱髓鞘疾病的发展加剧。但是，TLR3KO-SJL 小鼠的中枢神经系统中晚期而非早期抗病毒 CD4+和 CD8+T 细胞反应受到损害。然而，在病毒感染之前用 poly IC 激活 TLR3 也加剧了疾病的发展，而在病毒感染之后进行这种激活则抑制了疾病的发展。在病毒感染之前激活 TLR3 信号转导会阻碍保护性 IFN-γ产生的 CD4+和 CD8+T 细胞群体的诱导。相反，在病毒感染之后激活这些信号会改善 IFN-γ产生的 CD4+和 CD8+T 细胞的诱导。此外，用 poly IC 预处理的小鼠的中枢神经系统中表达的 PDL-1 和调节性 FoxP3+CD4+T 细胞增加，而用 poly IC 后处理的小鼠的中枢神经系统中表达的 PDL-1 和 FoxP3+CD4+T 细胞减少。
这些结果表明，TLR3 介导的信号转导在病毒感染期间通过降低病毒载量和调节免疫反应来防止脱髓鞘疾病。相反，在病毒感染之前过早激活 TLR3 信号转导会通过过度激活致病性免疫反应而导致发病机制。
