IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy.
IFNγ drives neuroinflammation, demyelination, and neurodegeneration in a mouse model of multiple system atrophy.
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干扰素γ在多系统萎缩的小鼠模型中导致神经炎症、脱髓鞘和神经变性。
DOI：
10.1186/s40478-023-01710-x
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发表时间：
2024-01-18
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
多系统萎缩症（MSA）是一种罕见的致命性突触核蛋白病，其特征是位于少突胶质细胞内的不溶性α-突触核蛋白（α-syn）胞浆包涵体。神经炎症、脱髓鞘和神经变性与神经胶质细胞质内含物（GCI）病理学区域相关，但是尚不清楚具体驱动疾病发病机制的是什么。最近的研究表明，在MSA患者的死后组织中发现的疾病病理可以通过过表达α-syn的修饰的AAV Olig 001-SYN在啮齿动物中建模，Olig 001-SYN对少突胶质细胞具有95%的向性。在Olig 001-SYN小鼠模型中，CD 4 + T细胞已被证明驱动神经炎症和脱髓鞘，但其发生机制仍不清楚。在这项研究中，我们在MSA的Olig 001-SYN模型中使用遗传学和药理学方法来证明促炎细胞因子干扰素γ（IFNγ）驱动神经炎症、脱髓鞘和神经变性。此外，使用IFNγ报告小鼠，我们发现浸润的CD 4 + T细胞是响应少突胶质细胞中α-syn过表达的IFNγ的主要产生者。这些研究的结果表明，来自CD 4 + T细胞的IFNγ表达驱动α-syn-mediated神经炎症、脱髓鞘和神经变性。这些结果表明，靶向IFNγ表达可能是MSA的潜在疾病修饰治疗策略。在线版本包含补充材料，可通过10.1186/s40478-023-01710-x获得。
Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (α-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of glia cytoplasmic inclusions (GCI) pathology, however it is not known what specifically drives disease pathogenesis. Recent studies have shown that disease pathologies found in post-mortem tissue from MSA patients can be modeled in rodents via a modified AAV overexpressing α-syn, Olig001-SYN, which has a 95% tropism for oligodendrocytes. In the Olig001-SYN mouse model, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs remains unclear. In this study we use genetic and pharmacological approaches in the Olig001-SYN model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFNγ) drives neuroinflammation, demyelination, and neurodegeneration. Furthermore, using an IFNγ reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFNγ in response to α-syn overexpression in oligodendrocytes. Results from these studies indicate that IFNγ expression from CD4+ T cells drives α-syn-mediated neuroinflammation, demyelination, and neurodegeneration. These results indicate that targeting IFNγ expression may be a potential disease modifying therapeutic strategy for MSA. The online version contains supplementary material available at 10.1186/s40478-023-01710-x.
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影响因子：
64.8
作者：
Filiano AJ;Xu Y;Tustison NJ;Marsh RL;Baker W;Smirnov I;Overall CC;Gadani SP;Turner SD;Weng Z;Peerzade SN;Chen H;Lee KS;Scott MM;Beenhakker MP;Litvak V;Kipnis J
通讯作者：
Kipnis J
T-BET的丧失，但不是STAT1阻止了实验性自身免疫性脑脊髓炎的发展。
影响因子：
15.3
作者：
Bettelli, E;Sullivan, B;Szabo, SJ;Sobel, RA;Glimcher, H;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.1007/s00702-021-02406-z
发表时间：
2021-10
期刊：
Journal of neural transmission (Vienna, Austria : 1996)
影响因子：
--
作者：
Lemos M;Wenning GK;Stefanova N
通讯作者：
Stefanova N
影响因子：
4.6
作者：
Jin, Mengmeng;Guenther, Rene;Ziemssen, Tjalf
通讯作者：
Ziemssen, Tjalf
影响因子：
6.1
作者：
Marmion, David J.;Rutkowski, Angela A.;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.