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磷酸化蛋白质组学鉴定神经退行性变中小胶质细胞 Siglec-F 的炎症反应。

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration.

机构信息

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

出版信息

Mol Syst Biol. 2020 Dec;16(12):e9819. doi: 10.15252/msb.20209819.

DOI:10.15252/msb.20209819
PMID:33289969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7722784/
Abstract

Alzheimer's disease (AD) is characterized by the appearance of amyloid-β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem cell-derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.

摘要

阿尔茨海默病（AD）的特征是在参与记忆的大脑区域出现淀粉样β斑块、神经原纤维缠结和炎症。我们使用质谱法对 CK-p25、5XFAD 和 Tau P301S 神经退行性变小鼠模型的磷酸化蛋白质组进行了定量分析。我们确定了一个涉及 Siglec-F 的共同反应，Siglec-F 在反应性小胶质细胞的亚群中上调。AD 中小胶质细胞中人类同源物 Siglec-8 也上调。Siglec-F 和 Siglec-8 在 BV-2 细胞系和人源性干细胞衍生的小胶质细胞模型中经干扰素γ（IFNγ）激活后上调。Siglec-F 过表达在 BV-2 细胞中激活依赖于唾液酸底物和免疫受体酪氨酸抑制基序（ITIM）磷酸化位点的内吞和细胞焦亡炎症反应。相关的人类 Siglec 也在 BV-2 细胞中引起类似反应。总之，我们的结果表明小鼠 Siglec-F 和人类 Siglec-8 在调节神经退行性变中小胶质细胞激活方面发挥着重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/36b3558fad02/MSB-16-e9819-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/39c9a64fe1ea/MSB-16-e9819-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/419acb00b16b/MSB-16-e9819-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/fd9e2d4f8407/MSB-16-e9819-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/61b9625962ac/MSB-16-e9819-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/7a4785e2ddb2/MSB-16-e9819-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/e141616017b2/MSB-16-e9819-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/20e865c26a6a/MSB-16-e9819-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/c96bf3281dad/MSB-16-e9819-g015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/3a812310481c/MSB-16-e9819-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/36b3558fad02/MSB-16-e9819-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/39c9a64fe1ea/MSB-16-e9819-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/4b62dffc6909/MSB-16-e9819-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/dd20e28e9d32/MSB-16-e9819-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/e1ae0503fd41/MSB-16-e9819-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/419acb00b16b/MSB-16-e9819-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/bbde7c0c45d9/MSB-16-e9819-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/fd9e2d4f8407/MSB-16-e9819-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/61b9625962ac/MSB-16-e9819-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/7a4785e2ddb2/MSB-16-e9819-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/e141616017b2/MSB-16-e9819-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/20e865c26a6a/MSB-16-e9819-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/c96bf3281dad/MSB-16-e9819-g015.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/930b/7722784/36b3558fad02/MSB-16-e9819-g012.jpg

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