Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.
Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.
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DOI：
10.1371/journal.pone.0140772
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hallenbeck JM
中科院分区：
文献类型：
--
作者：
Zhao J;Mou Y;Bernstock JD;Klimanis D;Wang S;Spatz M;Maric D;Johnson K;Klinman DM;Li X;Li X;Hallenbeck JM
免疫系统在中风的发展和病理学中起着重要作用。炎性小体是多蛋白复合物，已被认为是最终导致中风严重程度的炎症的关键参与者。炎性小体识别微生物和宿主来源的危险信号并激活半胱天冬酶-1，半胱天冬酶-1反过来控制促炎细胞因子IL-1β的产生。我们已经表明，A151，一种含有多个端粒TTAGGG基序的合成寡脱氧核苷酸，减少了活化的骨髓源性巨噬细胞产生IL-1β，这些巨噬细胞已经经历了氧-葡萄糖剥夺和LPS刺激。此外，我们证明A151降低了caspase-1和IL-1β的成熟，iNOS和NLRP 3蛋白的水平，以及这些细胞内线粒体膜电位的去极化。此外，我们已经证明，A151减少缺血性脑损伤和NLRP 3 mRNA水平的SHR-SP大鼠经历了永久性大脑中动脉闭塞。这些发现清楚地表明，通过A151调节炎性体活性可能有助于减少巨噬细胞产生的促炎细胞因子，巨噬细胞经历模拟脑缺血的条件，并调节中风动物模型中的缺血性脑损伤。因此，A151对缺血病理学的调节可能在开发新的中风预防和治疗策略中发挥作用。
The immune system plays a fundamental role in both the development and pathobiology of stroke. Inflammasomes are multiprotein complexes that have come to be recognized as critical players in the inflammation that ultimately contributes to stroke severity. Inflammasomes recognize microbial and host-derived danger signals and activate caspase-1, which in turn controls the production of the pro-inflammatory cytokine IL-1β. We have shown that A151, a synthetic oligodeoxynucleotide containing multiple telemeric TTAGGG motifs, reduces IL-1β production by activated bone marrow derived macrophages that have been subjected to oxygen-glucose deprivation and LPS stimulation. Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells. In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion. These findings clearly suggest that the modulation of inflammasome activity via A151 may contribute to a reduction in pro-inflammatory cytokine production by macrophages subjected to conditions that model brain ischemia and modulate ischemic brain damage in an animal model of stroke. Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.