嘌呤受体P2Y13调节小胶质细胞形态、功能及白细胞介素-1β的释放水平  

P2Y13 receptors regulate microglial morphology,surveillance, and resting levels of interleukin 1 release

作　　者：Kyrargyri V Madry C Rifat A Arancibia-Carcamo IL Jones SP Chan VTT Xu Y Robaye B Attwell D 杜一星 

机构地区：[1]Department of Neuroscience, Physiology, & Pharmacology, University College London [2]Department of Immunology, Laboratory of Molecular Genetics, Hellenic Pasteur Institute [3]Institute of Neurophysiology, Charité-Universitatsmedizin Berlin [4]Faculté de Médecine, Université Libre de Bruxelles [5]不详

出　　处：《神经损伤与功能重建》2019年第10期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：小胶质细胞利用一系列膜受体来感知周围环境。虽然已知P2Y12受体在小胶质细胞的突起向释放ATP/ADP的损伤部位的靶向运动定中起关键作用,但对P2Y13的作用知之甚少。转录组数据表明P2Y13是小胶质细胞中第2高表达的神经递质受体。本研究显示,在缺乏P2Y13受体小鼠的急性脑切片,膜片钳记录由ADP激活P2Y12受体引起的THIK-1 K+电流密度增加了约50%。这种增加表明P2Y12依赖的趋化性反应增强。但是在P2Y13敲除小鼠,P2Y12介导的小胶质细胞突起向充灌ADP的电极或激光融蚀点聚集所需的时间更长。解剖分析表明,在P2Y13敲除小鼠中,小胶质细胞的密度没有变化,但分枝较少,突起长度较短。因此在基因敲除的小鼠,小胶质细胞趋化的突起必须进一步生长然后才能到达靶标,且脑部监视降低了约30%。在P2Y13敲除小鼠脑片中,阻断P2Y12受体并不会影响监视,表明监视过程不需要这些高亲和力受体的补充激活。令人惊讶的是,在P2Y13敲除小鼠白细胞介素-1β释放的基础值增加了5倍,而LPS和ATP引起的释放不受影响;P2Y13敲除小鼠完整脑中的小胶质细胞未被检测到激活。因此,尽管P2Y13受体与P2Y12非常接近,但它们在调节小胶质细胞形态和功能方面起着不同的作用。Microglia sense their environment using an array of membrane receptors.While P2Y12receptors are known to play a key role in targeting directed motility of microglial processes to sites of damage where ATP/ADP is released,little is known about the role of P2Y13,which transcriptome data suggest is the second most expressed neurotransmitter receptor in microglia.We show that,in patch-clamp recordings in acute brain slices from mice lacking P2Y13receptors,the THIK-1 K+current density evoked by ADP activating P2Y12receptors was increased by^50%.This increase suggested that the P2Y12-dependent chemotaxis response should be potentiated;however,the time needed for P2Y12-mediated convergence of microglial processes onto an ADP-filled pipette or to a laser ablation was longer in the P2Y13KO.Anatomical analysis showed that the density of microglia was unchanged,but that they were less ramified with a shorter process length in the P2Y13KO.Thus,chemotactic processes had to grow further and so arrived later at the target,and brain surveillance was reduced by^30%in the knock-out.Blocking P2Y12receptors in brain slices from P2Y13KO mice did not affect surveillance,demonstrating that tonic activation of these high-affinity receptors is not needed for surveillance.Strikingly,baseline interleukin-1β release was increased fivefold while release evoked by LPS and ATP was not affected in the P2Y13KO,and microglia in intact P2Y13KO brains were not detectably activated.Thus,P2Y13receptors play a role different from that of their close relative P2Y12in regulating microglial morphology and function.

关 键 词：二磷酸腺苷 三磷酸腺苷 嘌呤受体P2Y12 嘌呤受体P2Y13 嘌呤能信号传递 

分 类 号：R741[医药卫生—神经病学与精神病学]