DNA sensors are expressed in astrocytes and microglia in vitro and are upregulated during gliosis in neurodegenerative disease.
DNA sensors are expressed in astrocytes and microglia in vitro and are upregulated during gliosis in neurodegenerative disease.
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作者：
Cox DJ;Field RH;Williams DG;Baran M;Bowie AG;Cunningham C;Dunne A
先天免疫系统对核酸的检测是病毒感染期间的基本宿主反应。近年来，已经鉴定了许多能够识别胞质DNA的免疫传感器，包括PYHIN家族成员AIM 2、IFI 16和p204以及酶cGAS。这些受体的激活导致抗病毒基因的诱导，包括1型干扰素和趋化因子，如CCL 5。我们已经在高度纯化的原代星形胶质细胞和小胶质细胞中对这些DNA传感器和PYHIN家族的其他成员进行了广泛的表达谱分析，并证明这两种细胞类型在mRNA水平上表达大多数这些蛋白质。在小胶质细胞中，几个家族成员响应于IFN-β治疗而高度上调，而两种细胞类型均诱导稳健的促炎和抗病毒细胞因子产生（例如，IL-6、CCL5、IFN-β）。IL-6的产生部分依赖于干扰素受体，IFN-β本身也是如此。此外，我们发现在慢性神经变性的鼠模型中，p204和AIM 2在体内以I型IFN依赖性方式上调。鉴于炎症反应导致神经元损伤的倾向，这些受体的表达和活化增加，不仅在病毒感染期间，而且在无菌炎症反应期间，有可能加剧现有的神经炎症，导致进一步的损伤和受损的神经发生。GLIA 2015;63：812-825
The detection of nucleic acids by the innate immune system is an essential host response during viral infection. In recent years, a number of immune sensors capable of recognizing cytosolic DNA have been identified and include the PYHIN family members AIM2, IFI16, and p204 as well as the enzyme, cGAS. Activation of these receptors leads to the induction of antiviral genes including Type‐1 interferons and chemokines such as CCL5. We have carried out extensive expression profiling of these DNA sensors and other members of the PYHIN family in highly purified primary astrocytes and microglia and have demonstrated that both cell types express the majority of these proteins at the mRNA level. In microglia, several family members are highly upregulated in response to IFN‐β treatment while both cell types induce robust proinflammatory and antiviral cytokine production (e.g., IL‐6, CCL5, IFN‐β) in the presence of immune stimulatory DNA and RNA. The production of IL‐6 is partially dependent on the interferon receptor as is IFN‐β itself. Furthermore, we have found that p204 and AIM2 are upregulated in a Type I IFN dependent fashion in vivo, in a murine model of chronic neurodegeneration. Given the propensity of inflammatory responses to cause neuronal damage, increased expression and activation of these receptors, not only during viral infection but also during sterile inflammatory responses, has the potential to exacerbate existing neuroinflammation leading to further damage and impaired neurogenesis. GLIA 2015;63:812–825