Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis.
Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis.
复制标题
DOI：
10.1186/s12974-023-02761-6
复制
发表时间：
2023-03-21
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
神经炎症是阿尔茨海默病（AD）的一个重要特征。了解免疫系统的哪些方面在 AD 中很重要可能会带来新的治疗方法。我们研究了主要的组织相容性复合物 I 类相关免疫分子 MR1，它被称为粘膜相关不变 T (MAIT) 细胞的先天样 T 细胞群识别。通过挖掘 Agora 数据库发现 AD 患者脑组织中 MR1 基因表达升高，我们试图研究 MR1/MAIT 细胞轴在 AD 病理学中的作用。使用 AD 患者的脑组织和 AD 的 5XFAD 小鼠模型，通过 qPCR、免疫荧光和流式细胞术分析 MR1 表达。此外，将缺乏 MR1 和 MAIT 细胞的小鼠与 5XFAD 小鼠杂交，产生一个模型来研究先天免疫轴的丧失如何改变 AD 进展。此外，5XFAD 小鼠还被用来研究大脑驻留的 MAIT 细胞随时间的变化。在 AD 患者和 5XFAD 小鼠的组织样本中，斑块周围小胶质细胞中的 MR1 表达较远处的小胶质细胞显着升高（人类 AD：P < 0.05；5XFAD：P < 0.001）。在缺乏 MR1/MAIT 细胞轴的 5XFAD 小鼠中，β-淀粉样蛋白斑块病理学的发展速度明显慢于那些具有 MR1 和 MAIT 细胞的小鼠。此外，在 5XFAD 小鼠的脑组织中，MAIT 细胞数量 (P<0.01) 及其激活状态暂时增加，后者是通过流式细胞术检测 CD69 (P<0.05) 和白细胞介素 2 受体 α 链 (P<0.05) 的上调来确定的。总之，这些数据揭示了 MR1/MAIT 细胞先天免疫轴在 AD 病理学中的先前未知的作用及其作为新型治疗靶点的潜在用途。在线版本包含可在 10.1186/s12974-023-02761-6 获取的补充材料。
Neuroinflammation is an important feature of Alzheimer’s disease (AD). Understanding which aspects of the immune system are important in AD may lead to new therapeutic approaches. We study the major histocompatibility complex class I-related immune molecule, MR1, which is recognized by an innate-like T cell population called mucosal-associated invariant T (MAIT) cells. Having found that MR1 gene expression is elevated in the brain tissue of AD patients by mining the Agora database, we sought to examine the role of the MR1/MAIT cell axis in AD pathology. Brain tissue from AD patients and the 5XFAD mouse model of AD were used to analyze MR1 expression through qPCR, immunofluorescence, and flow cytometry. Furthermore, mice deficient in MR1 and MAIT cells were crossed with the 5XFAD mice to produce a model to study how the loss of this innate immune axis alters AD progression. Moreover, 5XFAD mice were also used to study brain-resident MAIT cells over time. In tissue samples from AD patients and 5XFAD mice, MR1 expression was substantially elevated in the microglia surrounding plaques vs. those that are further away (human AD: P < 0.05; 5XFAD: P < 0.001). In 5XFAD mice lacking the MR1/MAIT cell axis, the development of amyloid-beta plaque pathology occurred at a significantly slower rate than in those mice with MR1 and MAIT cells. Furthermore, in brain tissue from 5XFAD mice, there was a temporal increase in MAIT cell numbers (P < 0.01) and their activation state, the latter determined by detecting an upregulation of both CD69 (P < 0.05) and the interleukin-2 receptor alpha chain (P < 0.05) via flow cytometry. Together, these data reveal a previously unknown role for the MR1/MAIT cell innate immune axis in AD pathology and its potential utility as a novel therapeutic target. The online version contains supplementary material available at 10.1186/s12974-023-02761-6.
登录
查看更多内容
影响因子：
4.5
作者：
Mechelli R;Romano S;Romano C;Morena E;Buscarinu MC;Bigi R;Bellucci G;Reniè R;Pellicciari G;Salvetti M;Ristori G
通讯作者：
Ristori G
影响因子：
14
作者：
通讯作者：
--
影响因子：
3.5
作者：
Sills, Joseph B.;Connors, Barry W.;Burwell, Rebecca D.
通讯作者：
Burwell, Rebecca D.
影响因子：
4.2
作者：
Jawhar, Sadim;Trawicka, Anna;Wirths, Oliver
通讯作者：
Wirths, Oliver
影响因子：
4.6
作者：
Lazarczyk, Maciej J.;Kemmler, Julia E.;Dickstein, Dara L.
通讯作者：
Dickstein, Dara L.