Repression of phagocytosis by human CD33 is not conserved with mouse CD33
Repression of phagocytosis by human CD33 is not conserved with mouse CD33
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DOI：
10.1038/s42003-019-0698-6
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发表时间：
2019-12-03
影响因子：
5.9
通讯作者：
Macauley, Matthew S.
中科院分区：
文献类型：
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作者：
Bhattacherjee, Abhishek;Rodrigues, Emily;Macauley, Matthew S.
CD33是一种免疫调节受体，通过调节小胶质细胞的吞噬作用与阿尔茨海默病(AD)的易感性有关。人CD33(HCD33)和小鼠CD33(MCD33)的不同特征包括mCD33中独特的跨膜赖氨酸和hCD33中的细胞质酪氨酸。这些差异在抑制吞噬作用方面的功能后果仍然知之甚少。使用一种新的α-mCD33单抗，我们发现mCD33在中性粒细胞上高水平表达，在小胶质细胞上低水平表达。值得注意的是，由于与mCD33中的跨膜赖氨酸相互作用，mCD33的细胞表面表达完全依赖于Dap12。在RAW264.7培养的巨噬细胞、BV-2培养的小胶质细胞、原代新生和成人小胶质细胞中，mCD33的基因消融不会改变对货物的摄取，包括聚集的Aβ(1-42)。或者，单核细胞系中hCD33的缺失增加了货物摄取。此外，在小胶质细胞系中表达hCD33的转基因小鼠在原代小胶质细胞中表现出对Cargo摄取的抑制。因此，mCD33和hCD33在调节吞噬功能方面具有不同的作用，突显了研究hCD33在AD易感性中的重要性。
CD33 is an immunomodulatory receptor linked to Alzheimer's disease (AD) susceptibility via regulation of phagocytosis in microglia. Divergent features between human CD33 (hCD33) and murine CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new alpha mCD33 monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. Notably, cell surface expression of mCD33 is entirely dependent on Dap12 due to an interaction with the transmembrane lysine in mCD33. In RAW264.7 cultured macrophages, BV-2 cultured microglia, primary neonatal and adult microglia, uptake of cargo - including aggregated A beta(1-42) - is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis, highlighting the importance of studying hCD33 in AD susceptibility.