The development of neuroinflammation, as well as the progression of several neurodegenerative diseases, has been associated with the activation and mobilization of the peripheral immune system due to systemic inflammation. However, the mechanism by which this occurs remains unclear. Herein, we addressed the effect of systemic, endotoxin-free induced-co-expression of IL-12 and IL-18 in the establishment of a novel cytokine-mediated model of neuroinflammation. Following peripheral hydrodynamic shear of IL-12 plus IL-18 cDNAs in C57BL/6 mice, we induced systemic and persistent level of IL-12, which in turn promoted the elevation of circulating pro-inflammatory cytokines TNF-α and IFN-γ, accompanied with splenomegaly. Moreover, even though we identified an increased gene expression of both TNF-α and IFN-γ in the brain, only TNF-α was shown to be dispensable, revealing an IFN-γ-dependent activation of microglia and the recruitment of leukocytes, particularly of highly activated inflammatory monocytes. Taken together, our results argue for a systemic cytokine-mediated establishment and development of neuroinflammation, having identified IFN-γ as a potential target for immunotherapy.

中文翻译：

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IL-12和IL-18的系统性无菌诱导共表达可驱动IFN-γ依赖性小胶质细胞的活化，并将表达MHC-II的炎性单核细胞募集入大脑。

由于系统性炎症，神经炎症的发展以及几种神经退行性疾病的进展与周围免疫系统的激活和动员有关。但是，发生这种情况的机制仍不清楚。在这里，我们解决了IL-12和IL-18的全身性，无内毒素诱导的共表达在建立新型细胞因子介导的神经炎症模型中的作用。在C57BL / 6小鼠中IL-12和IL-18 cDNA的周围流体动力剪切之后，我们诱导了IL-12的系统性和持久性水平，进而促进了循环中促炎性细胞因子TNF-α和IFN-γ的升高，伴有脾肿大。而且，即使我们发现大脑中TNF-α和IFN-γ的基因表达均增加，仅TNF-α被证明是可有可无的，揭示了小胶质细胞的IFN-γ依赖性活化和白细胞，特别是高度活化的炎性单核细胞的募集。综上所述，我们的结果证明了系统性细胞因子介导的神经炎症的建立和发展，已经确定IFN-γ是免疫疗法的潜在靶标。