Inhibition of P2X4R attenuates white matter injury in mice after intracerebral hemorrhage by regulating microglial phenotypes.
Inhibition of P2X4R attenuates white matter injury in mice after intracerebral hemorrhage by regulating microglial phenotypes.
复制标题
抑制 P2X4R 通过调节小胶质细胞表型减轻脑出血后小鼠白质损伤。
DOI：
10.1186/s12974-021-02239-3
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发表时间：
2021-08-23
影响因子：
9.3
通讯作者：
Yan F
中科院分区：
文献类型：
--
作者：
Fu X;Zhou G;Wu X;Xu C;Zhou H;Zhuang J;Peng Y;Cao Y;Zeng H;Li Y;Li J;Gao L;Chen G;Wang L;Yan F
脑白色物质损伤（White matter injury，ICH）是与脑出血（intracerebral hemorrhage，ICH）相关的主要神经病理学事件。P2 X嘌呤受体4（P2 X4 R）是P2 X嘌呤受体家族的一员，在中枢神经系统疾病中起着重要的调节作用。我们的研究探讨了P2 X4 R在小鼠脑出血后的脑水肿和炎症反应中的作用，以及可能的作用机制。通过注射胶原酶在小鼠中诱导ICH。用5-BDBD和ANA-12处理小鼠以分别抑制P2 X4 R和原肌球蛋白相关激酶受体B（Trk B）。免疫组化和定量聚合酶链反应（qPCR）检测P2 X4 R抑制后的小胶质细胞表型。免疫印迹（WB）和免疫组化染色用于检查的ESTA和潜在的分子机制。进行了圆柱，拐角，钢丝悬挂和前肢放置测试，以评估神经行为功能。脑出血后P2 X4 R蛋白表达上调，尤以脑出血后第7天最为明显，主要定位于小胶质细胞。通过5-BDBD抑制P2 X4 R促进ICH后神经功能恢复以及ICH诱导的促炎性小胶质细胞转化为抗炎表型，并减弱ICH诱导的炎症反应。此外，我们发现TrkB阻断可以逆转脑保护作用以及5-BDBD治疗后的神经保护作用。这一结果表明，P2 X4 R在调节脑出血和神经炎症中起着至关重要的作用，P2 X4 R抑制可能有益于ICH患者。我们的研究结果表明，P2 X4 R有助于通过极化小胶质细胞到一个促炎表型后ICH复发。此外，P2 X4 R的抑制促进促炎性小胶质细胞极化为抗炎表型，增强脑源性神经营养因子（BDNF）的产生，并通过BDNF/TrkB途径，减弱炎症并改善神经功能。因此，调节P2 X4 R的激活可能有助于减轻ICH所致的脑损伤。在线版本包含补充材料，可通过10.1186/s12974-021-02239-3获得。
White matter injury (WMI) is a major neuropathological event associated with intracerebral hemorrhage (ICH). P2X purinoreceptor 4 (P2X4R) is a member of the P2X purine receptor family, which plays a crucial role in regulating WMI and neuroinflammation in central nervous system (CNS) diseases. Our study investigated the role of P2X4R in the WMI and the inflammatory response in mice, as well as the possible mechanism of action after ICH. ICH was induced in mice via collagenase injection. Mice were treated with 5-BDBD and ANA-12 to inhibit P2X4R and tropomyosin-related kinase receptor B (TrkB), respectively. Immunostaining and quantitative polymerase chain reaction (qPCR) were performed to detect microglial phenotypes after the inhibition of P2X4R. Western blots (WB) and immunostaining were used to examine WMI and the underlying molecular mechanisms. Cylinder, corner turn, wire hanging, and forelimb placement tests were conducted to evaluate neurobehavioral function. After ICH, the protein levels of P2X4R were upregulated, especially on day 7 after ICH, and were mainly located in the microglia. The inhibition of P2X4R via 5-BDBD promoted neurofunctional recovery after ICH as well as the transformation of the pro-inflammatory microglia induced by ICH into an anti-inflammatory phenotype, and attenuated ICH-induced WMI. Furthermore, we found that TrkB blockage can reverse the protective effects of WMI as well as neuroprotection after 5-BDBD treatment. This result indicates that P2X4R plays a crucial role in regulating WMI and neuroinflammation and that P2X4R inhibition may benefit patients with ICH. Our results demonstrated that P2X4R contributes to WMI by polarizing microglia into a pro-inflammatory phenotype after ICH. Furthermore, the inhibition of P2X4R promoted pro-inflammatory microglia polarization into an anti-inflammatory phenotype, enhanced brain-derived neurotrophic factor (BDNF) production, and through the BDNF/TrkB pathway, attenuated WMI and improved neurological function. Therefore, the regulation of P2X4R activation may be beneficial for the reducing of ICH-induced brain injury. The online version contains supplementary material available at 10.1186/s12974-021-02239-3.
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DOI：
10.1016/j.bbi.2016.12.012
发表时间：
2017-03
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Lan X;Han X;Li Q;Li Q;Gao Y;Cheng T;Wan J;Zhu W;Wang J
通讯作者：
Wang J
影响因子：
5.3
作者：
Fletcher, Jessica L.;Dill, Larissa K.;Semple, Bridgette D.
通讯作者：
Semple, Bridgette D.
影响因子：
9.3
作者：
Feng L;Chen Y;Ding R;Fu Z;Yang S;Deng X;Zeng J
通讯作者：
Zeng J
影响因子：
5.3
作者：
He, Junchi;Huang, Yike;Cheng, Chongjie
通讯作者：
Cheng, Chongjie
影响因子：
8.3
作者：
Hua, Y;Schallert, T;Xi, GH
通讯作者：
Xi, GH