Department of General Physiology and Biophysics, Faculty of Biology University of Belgrade, Studentski trg 3, Belgrade 11001, Serbia.
Pharmacol Res. 2019 Jun;144:99-115. doi: 10.1016/j.phrs.2019.04.007. Epub 2019 Apr 5.
The review summarizes available data regarding the complex regulation of CD73 at the neurovascular unit (NVU) during neuroinflammation. Based on available data we propose the biphasic pattern of CD73 regulation at NVU, with an early attenuation and a postponed up-regulation of CD73 activity. Transient attenuation of CD73 activity on leukocyte/vascular endothelium and leukocyte/astrocyte surface, required for the initiation of a neuroinflammatory response, may be effectuated either by catalytic inhibition of CD73 and/or by shedding of the CD73 molecule from the cell surface, while postponed induction of CD73 is effectuated by transcriptional up-regulation of Nt5e and posttranslational modifications. Neuroinflammatory conditions are also associated with significant enhancement and gain-of-function of AR-mediated adenosine signaling. However, in contrast to the temporary prevalence of AR over AR signaling during an acute inflammatory response, prolonged induction of AR and resulting perpetual CD73/AR coupling may be a contributing factors in the transition between acute and chronic neuroinflammation. Thus, pharmacological targeting of the CD73/AR axis may attenuate inflammatory response and ameliorate neurological deficits in chronic neuroinflammatory conditions.
该综述总结了神经血管单元 (NVU) 中神经炎症期间 CD73 复杂调节的现有数据。基于现有数据，我们提出了 NVU 中 CD73 调节的双相模式，其活性早期减弱，随后延迟上调。白细胞/血管内皮细胞和白细胞/星形胶质细胞表面上 CD73 活性的短暂衰减，对于神经炎症反应的启动是必需的，可能通过 CD73 的催化抑制和/或 CD73 分子从细胞表面脱落来实现，而 CD73 的延迟诱导则通过 Nt5e 的转录上调和翻译后修饰来实现。神经炎症状态还与 AR 介导的腺苷信号的显著增强和功能获得相关。然而，与急性炎症反应期间 AR 对 AR 信号的短暂优势相反，AR 的长期诱导以及由此产生的持续的 CD73/AR 偶联可能是急性和慢性神经炎症之间转变的一个促成因素。因此，靶向 CD73/AR 轴的药理学方法可能会减弱炎症反应，并改善慢性神经炎症状态下的神经功能缺损。
