Owens Trevor, Babcock Alicia A, Millward Jason M, Toft-Hansen Henrik
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Quebec, Canada.
Brain Res Brain Res Rev. 2005 Apr;48(2):178-84. doi: 10.1016/j.brainresrev.2004.12.007. Epub 2005 Jan 12.
The distinction between immune-regulatory and effector cytokines and chemokines, and neural growth and survival factors (neurotrophins) becomes increasingly blurred. We discuss here the role of immune cytokines and chemokines as mediators of innate glial responses in the central nervous system. Glial responses to axonal degeneration in the hippocampus dentate gyrus are initiated independently of immune involvement, following transection of afferent entorhinal (perforant path) axons. The glial responses that we measure involve early microglial and somewhat later astrocyte activations. Among the earliest responses are the expression of a wide profile of chemokines, and of the cytokine tumor necrosis factor-alpha (TNFalpha). The cytokine interferon-gamma (IFNgamma) is not normally produced in the CNS, but TNFalpha levels are enhanced if it is present. Viral vector-derived IFNgamma directly induces the expression of chemokines in the CNS, in the absence of any other inflammatory event, but the profiles differ from those induced by axotomy. Chemokines that bind the CCR2 receptor are implicated in traffic of macrophages and T cells to the denervated hippocampus. Innate responses in the immune system are directed by Toll-like receptors (TLR). Our recent studies focus on specific TLR signals as upstream on-switches for glial cytokine and chemokine responses. The biological activity of chemokines is regulated by matrix metalloproteinase enzymes (MMPs) and specific members of this family are expressed in response to axonal lesioning. These findings strengthen the case for the sharing of signals between the immune and nervous system.
免疫调节性细胞因子、效应细胞因子、趋化因子与神经生长及存活因子（神经营养因子）之间的区别正变得越来越模糊。我们在此讨论免疫细胞因子和趋化因子作为中枢神经系统中先天性胶质细胞反应介质的作用。海马齿状回中轴突退化所引发的胶质细胞反应，是在传入内嗅（穿通通路）轴突横断后独立于免疫参与而启动的。我们所测量的胶质细胞反应包括早期的小胶质细胞激活以及稍晚些时候的星形胶质细胞激活。最早的反应之一是多种趋化因子以及细胞因子肿瘤坏死因子-α（TNFα）的表达。细胞因子干扰素-γ（IFNγ）通常不在中枢神经系统中产生，但如果它存在，TNFα水平会升高。病毒载体衍生的IFNγ在没有任何其他炎症事件的情况下直接诱导中枢神经系统中趋化因子的表达，但其表达谱与轴突切断所诱导的不同。与CCR2受体结合的趋化因子与巨噬细胞和T细胞向去神经支配的海马体的迁移有关。免疫系统中的先天性反应由Toll样受体（TLR）引导。我们最近的研究聚焦于特定的TLR信号，将其作为胶质细胞因子和趋化因子反应的上游启动开关。趋化因子的生物活性由基质金属蛋白酶（MMP）调节，并且该家族的特定成员会在轴突损伤时表达。这些发现进一步证明了免疫和神经系统之间信号共享的情况。
