PARP14 inhibits microglial activation via LPAR5 to promote post-stroke functional recovery
PARP14 inhibits microglial activation via LPAR5 to promote post-stroke functional recovery
复制标题
DOI：
10.1080/15548627.2020.1847799
复制
发表时间：
2020-12
期刊：
影响因子：
13.3
通讯作者：
Ying Tang;Jinchang Liu;Yu Wang;Li Yang;B. Han;Yuan Zhang;Ying Bai;Ling Shen;Mingyue Li-Mingyue
中科院分区：
文献类型：
--
作者：
Ying Tang;Jinchang Liu;Yu Wang;Li Yang;B. Han;Yuan Zhang;Ying Bai;Ling Shen;Mingyue Li-Mingyue
摘要：中风是一个重大的公共卫生问题，导致全世界高死亡率和致残率，但目前除了使用 PLAT（纤溶酶原激活剂，组织）外，尚无有效的药物治疗方法。在这里，我们发现 PARP14（聚（ADP-核糖）聚合酶家族，成员 14）水平在光血栓性中风（PT）小鼠的梗塞周围区域显着增加。 PARP14 的基因敲除和药物抑制会加重 PT 小鼠的功能损伤并增加梗塞体积，而 PARP14 的过度表达则表现出相反的效果。此外，小胶质细胞中 PARP14 丰富，PARP14 的下调增加了中风后小胶质细胞的激活，而 PARP14 的过度表达可能通过小胶质细胞巨自噬/自噬调节减轻了小胶质细胞的激活。从机制上讲，PARP14 的过度表达会抑制 Lpar5（溶血磷脂酸受体 5）基因转录，从而抑制中风后小胶质细胞的激活。综上所述，PARP14是一种中风诱导信号，可限制小胶质细胞激活并促进功能恢复，可作为开发新中风治疗药物的新靶点。此外，这些发现可能有助于正确使用各种 PARP 抑制剂。缩写：3-MA：3-甲基腺嘌呤； AIF1/Iba-1：同种异体移植物炎症因子1； CNS：中枢神经系统； CQ：氯喹； DAPI：4ʹ,6-二脒基-2-苯基吲哚； DMEM：Dulbecco 改良的 Eagle 培养基； DMSO：二甲亚砜； ELISA：酶联免疫吸附测定； FBS：胎牛血清； GFAP: 胶质原纤维酸性蛋白； IL1B/IL-1β：白细胞介素1β； IL6/IL-6：白细胞介素6； LPAR5：溶血磷脂酸受体5； MAP1LC3B：微管相关蛋白1轻链3β； NOS2/iNOS：一氧化氮合酶 2，诱导型； OGD：氧糖剥夺； PAR：聚（ADP核糖）的聚合物； PARP：聚（ADP-核糖）聚合酶家族； PBS：磷酸盐缓冲盐水； PLAT/tPA：纤溶酶原激活剂，组织； PT：光血栓性中风； qPCR：定量聚合酶链式反应；说唱：雷帕霉素； RBFOX3/NeuN：RNA 结合蛋白，fox-1 同源物（秀丽隐杆线虫）3； SQSTM1: 隔离体 1; TNF/TNF-α：肿瘤坏死因子
ABSTRACT Stroke is a major public health problem leading to high rates of death and disability worldwide, but no effective pharmacological therapy is currently available except for the use of PLAT (plasminogen activator, tissue). Here we show that PARP14 (poly (ADP-ribose) polymerase family, member 14) level was significantly increased in the peri-infarct zone of photothrombotic stroke (PT) mice. Genetic knockdown and pharmacological inhibition of PARP14 aggravated functional impairment and increased infarct volume in PT mice, while overexpression of PARP14 displayed the opposite effects. Furthermore, PARP14 was abundant in microglia, and downregulation of PARP14 increased post-stroke microglial activation, whereas overexpression of PARP14 alleviated microglial activation, possibly through microglial macroautophagy/autophagy modulation. Mechanistically, overexpression of PARP14 suppressed Lpar5 (lysophosphatidic acid receptor 5) gene transcription to inhibit microglial activation post stroke. Taken together, PARP14 is a stroke-induced signal that restricts microglial activation and promotes functional recovery, and can serve as a novel target to develop new therapeutic agents for stroke. Moreover, these findings may be conducive to proper use of various PARP inhibitors. Abbreviations: 3-MA: 3-methyladenine; AIF1/Iba-1: allograft inflammatory factor 1; CNS: central nervous system; CQ: chloroquine; DAPI: 4ʹ,6-diamidino-2-phenylindole; DMEM: Dulbecco’s modified Eagle’s medium; DMSO: dimethyl sulfoxide; ELISA: enzyme-linked immunosorbent assay; FBS: fetal bovine serum; GFAP: glial fibrillary acidic protein; IL1B/IL-1β: interleukin 1 beta; IL6/IL-6: interleukin 6; LPAR5: lysophosphatidic acid receptor 5; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; NOS2/iNOS: nitric oxide synthase 2, inducible; OGD: oxygen glucose deprivation; PAR: polymer of poly (ADP ribose); PARP: poly (ADP-ribose) polymerase family; PBS: phosphate-buffered saline; PLAT/tPA: plasminogen activator, tissue; PT: photothrombotic stroke; qPCR: quantitative polymerase chain reaction; Rap: rapamycin; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SQSTM1: sequestosome 1; TNF/TNF-α: tumor necrosis factor