Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.
Silencing IFN-γ binding/signaling in astrocytes versus microglia leads to opposite effects on central nervous system autoimmunity.
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DOI：
10.4049/jimmunol.1303321
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发表时间：
2015-05-01
期刊：
影响因子：
--
通讯作者：
Rostami A
中科院分区：
文献类型：
--
作者：
Ding X;Yan Y;Li X;Li K;Ciric B;Yang J;Zhang Y;Wu S;Xu H;Chen W;Lovett-Racke AE;Zhang GX;Rostami A
IFN-γ 是 Th1 细胞的标志性细胞因子，在实验性自身免疫性脑脊髓炎 (EAE)（一种多发性硬化症 (MS) 动物模型）中发挥着重要作用。迄今为止，IFN-γ 在 EAE 中的作用主要是通过其对免疫细胞的影响来研究的，而对其对中枢神经系统 (CNS) 细胞（尤其是在体内）的影响知之甚少。在这项研究中，我们剖析了星形胶质细胞和小胶质细胞中 IFN-γ 结合/信号传导的体内效应和机制，发现这些细胞类型中的 IFN-γ 信号传导在 EAE 发病机制中具有相反的作用。沉默星形胶质细胞中的 IFN-γ 结合/信号传导可改善 EAE，而在小胶质细胞中，可能在某些浸润性巨噬细胞中，则会增加疾病的严重程度。沉默星形胶质细胞中的 IFN-γ 信号传导会导致趋化因子表达减少，并减少浸润到中枢神经系统的炎症细胞，同时阻断小胶质细胞中的 IFN-γ 结合/信号传导，可能还会浸润巨噬细胞，通过增强小胶质细胞的激活和增殖来增加疾病的严重程度。此外，阻断星形胶质细胞中的 IFN-γ 结合/信号传导可改善 Th1 和 Th17 介导的过继性 EAE，表明星形胶质细胞中的 IFN-γ 信号传导在自身免疫性 CNS 炎症中发挥重要作用。因此，我们的研究定义了 IFN-γ 在 EAE 发病机制中的新作用机制，并强调了开发针对 CNS 细胞的 MS 疗法的机会。
IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, while much less is known about its effects on central nervous system (CNS) cells, especially in vivo. In this study we dissected the in vivo effects and mechanisms of IFN-γ binding/signaling in astrocytes and microglia and found that IFN-γ signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-γ binding/signaling in astrocytes ameliorated EAE, while in microglia, and likely in some infiltrating macrophages, it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, while blocking IFN-γ binding/signaling in microglia, probably infiltrating macrophages as well, increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ binding/signaling in astrocytes ameliorated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of MS therapies directed at CNS cells.
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影响因子：
32.4
作者：
Kang Z;Altuntas CZ;Gulen MF;Liu C;Giltiay N;Qin H;Liu L;Qian W;Ransohoff RM;Bergmann C;Stohlman S;Tuohy VK;Li X
通讯作者：
Li X
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Hindinger C;Bergmann CC;Hinton DR;Phares TW;Parra GI;Hussain S;Savarin C;Atkinson RD;Stohlman SA
通讯作者：
Stohlman SA
影响因子：
4.4
作者：
Ebner, Friederike;Brandt, Christine;Nitsch, Robert
通讯作者：
Nitsch, Robert
影响因子：
100.3
作者：
Baxter, Alan G.
通讯作者：
Baxter, Alan G.