Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation.
Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation.
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通过P2RX4激活，溶物磷脂酰胆碱的持续升高通过小胶质细胞募集来促进辐射脑坏死。
DOI：
10.1038/s41598-022-12293-3
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发表时间：
2022-05-24
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
脑放射性坏死(RN)或神经认知障碍是恶性脑肿瘤或头颈癌放射治疗后可能发生的严重不良反应。RN伴随导致浮肿或微出血的炎症，目前还没有开发出根本性的治疗方法。在炎症中，溶血磷脂(LPLs)由磷脂酶A2产生，在动脉粥样硬化或脑疾病的无菌炎症中发挥生物活性脂类的作用。为了阐明其潜在的机制，我们研究了溶血磷脂(LPLs)与RN发育之间的可能联系，即通过嘌呤能受体P2X嘌呤受体4(P2RX4)激活小胶质细胞。我们先前建立了RN的小鼠模型，在本研究中，用LC-MS/MS分析了RN模型小鼠脑内磷脂和脂蛋白的含量。免疫组织化学染色显示RN模型大鼠脑内小胶质细胞和P2RX4的表达呈时程变化。我们用P2RX4的变构调节剂伊维菌素治疗RN模型小鼠，观察其对P2RX4和LPLs产生的小胶质细胞激活的影响，以及由此产生的对总体存活率和工作记忆的影响。我们发现，在伴有小胶质细胞积聚的RN进展过程中，LPL(溶血磷脂酰胆碱(LPC)、溶血磷脂酰胆碱(LPC)、溶血磷脂酰丝氨酸、溶血磷脂酰乙醇胺、溶血磷脂酰肌醇和溶血磷脂酰甘油)保持在较高水平，但磷脂升高有限。伊维菌素可抑制小胶质细胞的积聚和对P2RX4的激活。此外，伊维菌素对除LPC外的所有LPL的抬高也有抑制作用。然而，存活时间的延长和工作记忆障碍的改善是有限的。我们的发现表明，无法控制的LPC增加，即使使用伊维菌素治疗，也会促进RN和工作记忆障碍的发展。因此，抑制LPC对于控制RN和放射治疗后的神经认知障碍至关重要。
Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A2 and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC–MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs’ production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy.
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影响因子：
13.6
作者：
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通讯作者：
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影响因子：
1.8
作者：
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通讯作者：
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影响因子：
2
作者：
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DOI：
10.1186/1550-2783-8-16
发表时间：
2011-10-21
影响因子：
5.1
作者：
Parker AG;Gordon J;Thornton A;Byars A;Lubker J;Bartlett M;Byrd M;Oliver J;Simbo S;Rasmussen C;Greenwood M;Kreider RB
通讯作者：
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DOI：
10.1161/atvbaha.115.306964
发表时间：
2016-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Li X;Fang P;Li Y;Kuo YM;Andrews AJ;Nanayakkara G;Johnson C;Fu H;Shan H;Du F;Hoffman NE;Yu D;Eguchi S;Madesh M;Koch WJ;Sun J;Jiang X;Wang H;Yang X
通讯作者：
Yang X