Astrocytic Lrp4 (Low-Density Lipoprotein Receptor-Related Protein 4) Contributes to Ischemia-Induced Brain Injury by Regulating ATP Release and Adenosine-A(2A)R (Adenosine A2A Receptor) Signaling.
Astrocytic Lrp4 (Low-Density Lipoprotein Receptor-Related Protein 4) Contributes to Ischemia-Induced Brain Injury by Regulating ATP Release and Adenosine-A(2A)R (Adenosine A2A Receptor) Signaling.
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星形胶质细胞 Lrp4（低密度脂蛋白受体相关蛋白 4）通过调节 ATP 释放和腺苷 A2AR（腺苷 A2A 受体）信号传导导致缺血性脑损伤。
DOI：
10.1161/strokeaha.117.018115
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发表时间：
2018-01
期刊：
影响因子：
8.3
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Ye XC;Hu JX;Li L;Li Q;Tang FL;Lin S;Sun D;Sun XD;Cui GY;Mei L;Xiong WC
低密度脂蛋白受体相关蛋白4（Lrp 4）主要在星形胶质细胞中表达，通过抑制ATP释放来调节谷氨酸能神经传递。在这里，我们研究了Lrp 4在缺血/中风诱导的脑损伤反应中的功能，包括谷氨酸诱导的神经元死亡和反应性星形胶质细胞增生。对脑特异性Lrp 4条件性敲除（CKO）小鼠（Lrp 4GFAP-Cre）、星形胶质细胞特异性Lrp 4-CKO小鼠（Lrp 4GFAP-creER）及其对照小鼠（Lrp 4f/f）进行光血栓性缺血和/或短暂性大脑中动脉闭塞（MCAo）。在缺血/中风后，对小鼠或其脑样品进行行为测试、脑组织学、免疫荧光染色、Western印迹和定量实时（qRT）-PCR分析。此外，将原代星形胶质细胞和神经元在有或没有氧和葡萄糖剥夺（OGD）以及存在或不存在腺苷-A2 AR或ATP-P2 X7 R信号传导的拮抗剂的情况下共培养。还测定了培养星形胶质细胞的条件培养基（CM）中的胶质递质，如谷氨酸、D-丝氨酸、ATP和腺苷。Lrp 4主要在星形胶质细胞中表达，在缺血/中风时增加。Lrp 4GFAP-Cre和Lrp 4GFAP-creER小鼠的脑损伤均较少，包括神经元死亡减少和反应性星形胶质细胞增生受损。从机制上讲，星形胶质细胞中的Lrp 4-CKO增加了ATP的释放和ATP衍生物腺苷的产生，而OGD进一步提高了ATP的释放和腺苷的产生。ATP-P2 X7 R或腺苷-A2 AR信号传导的药理学抑制减弱了Lrp 4GFAP-creER的保护作用。星形胶质细胞Lrp 4在缺血性脑损伤反应中起重要作用。星形胶质细胞中Lrp 4缺陷似乎对缺血性脑损伤具有保护作用，这可能是由于ATP释放和腺苷-A2 AR信号传导增加。
Low-density lipoprotein receptor-related protein 4 (Lrp4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. The brain-specific Lrp4-conditional knock-out (CKO) mice (Lrp4GFAP-Cre), astrocytic specific Lrp4-CKO mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and/or the transient middle cerebral artery occlusion (MCAo). After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time (qRT)-PCR analyses. In addition, primary astrocytes and neurons were co-cultured with or without oxygen and glucose deprivation (OGD) and in the presence or absence of the antagonist for adenosine-A2AR or ATP-P2X7R signaling. Gliotransmitters, such as glutamate, D-serine, ATP, and adenosine, in the condition medium (CM) of cultured astrocytes were also measured. Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4-CKO in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by OGD. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER’s protective effect. The astrocytic Lrp4 plays an important role in ischemic brain injuring response. Lrp4-deficiency in astrocytes appears to be protective in response to ischemic brain injury, likely due to the increased ATP release and adenosine-A2AR signaling.