Natural Killer Cells Disrupt Nerve Fibres through Granzyme H in Atheriosclerotic Cerebral Small Vessel Disease.
Natural Killer Cells Disrupt Nerve Fibres through Granzyme H in Atheriosclerotic Cerebral Small Vessel Disease.
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DOI：
10.1093/gerona/glac173
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Zhengqi Lu
中科院分区：
文献类型：
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作者：
Dafan Yu;Wei Cai;Xiaodong Chen;Danli Lu;Mengyan Hu;Tingting Lu;Bing Qin;Aimin Wu;Hengfang Ruan;Yaxin Lu;Zifeng Liu;Lei Wei;Zhengqi Lu
Natural killer (NK) cells are enriched in the central nervous system in aging-related atheriosclerotic cerebral small vessel disease (aCSVD), but their roles and underlying mechanism remain to be elucidated. To identify potential cytotoxic molecules released by NK cells in aCSVD lesions, proteomic analysis of cerebrospinal fluid (CSF), plasma, and peripheral NK cells from patients with aCSVD were performed. We found that integrin β2 (ITGB2), cathepsin D (CTSD), and granzyme H (GZMH) were highly expressed in NK cells. ITGB2 interacted with intercellular adhesion molecule 1 in vascular endothelial cells. As assessed by immunofluorescence and scanning electron microscopy of the blood-brain barrier model, transwell membranes covered with primary human brain microvascular endothelial cells and astrocytes, we demonstrated that the CTSD-mediated degradation of collagen in the blood-brain barrier depended on the cytotoxicity of NK cells in aCSVD. With the immunostaining in vitro and vivo, GZMH disruption of demyelinated nerve fibres was reversed by cotreatment with the inhibitor 3,4-DCIC during white matter hyperintensity (WMH) in aCSVD. Our results indicate that NK cells contribute to CTSD-induced damage to the blood-brain barrier and GZMH-induced disruption of nerve fibres during WMH in aCSVD.
