MicroRNA-152 attenuates neuroinflammation in intracerebral hemorrhage by inhibiting thioredoxin interacting protein (TXNIP)-mediated NLRP3 inflammasome activation
MicroRNA-152 attenuates neuroinflammation in intracerebral hemorrhage by inhibiting thioredoxin interacting protein (TXNIP)-mediated NLRP3 inflammasome activation
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MicroRNA-152 通过抑制硫氧还蛋白相互作用蛋白 (TXNIP) 介导的 NLRP3 炎症小体激活来减轻脑出血中的神经炎症。
DOI：
10.1016/j.intimp.2019.106141
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发表时间：
2020-03-01
影响因子：
5.6
通讯作者：
He, Zhiyi
中科院分区：
文献类型：
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作者：
Hu, Liuting;Zhang, Heyu;He, Zhiyi
脑出血后神经炎症反应是脑损伤和神经功能恶化的重要原因。据报道，MicroRNA-152（miR-152）在ICH患者中下调，并在其他疾病中具有抗炎特性。本研究采用胶原酶诱导的大鼠脑出血模型和氯化血红素暴露的细胞模型，探讨miR-152在脑出血中的作用及其机制。我们首先证实了miR-152在两种模型中一致下调。miR-152在小胶质细胞BV2细胞中的过表达减少了hernin诱导的炎症反应和活性氧（ROS）的产生，从而保护了共培养的神经元HT 22细胞。此外，通过脑室内慢病毒注射在ICH大鼠中过表达miR-152显著减轻神经损伤、脑水肿和血肿。这些变化与ICH诱导的神经元死亡显著减少相关，如NeuN和TUNEL共染色所示，与ICH诱导的神经炎症相关，如炎症细胞因子水平以及血肿周围区域Iba1阳性染色细胞的数量所示。在机制上，miR-152显著抑制ICH诱导的TXNIP表达，并且其过表达阻断TXNIP与NOD样受体pyrin domain containing 3（NLRP 3）之间的相互作用，从而抑制NLRP 3驱动的炎性小体激活以减轻体内和体外神经炎症。此外，si-TXNIP转染的结果进一步证实了TXNIP抑制参与了miR-152过表达引起的NLRP 3炎性小体激活的减少。总的来说，本研究表明，miR-152通过抑制TXNIP介导的NLRP 3炎性小体激活来保护ICH诱导的神经炎症和脑损伤，这表明了ICH治疗的潜在策略。
Neuroinflammation significantly contributes to brain injury and neurological deterioration following intracerebral hemorrhage (ICH). MicroRNA-152(miR-152) was reported to be downregulated in ICH patients and to possess and-inflammatory properties in other diseases. In this study, we aimed to explore the role of miR-152 in ICH, and the underlying mechanisms, using a collagenase-induced rat ICH model and hemin-exposure as a cell model. We first confirmed that miR-152 was consistently downregulated in both models. Overexpression of miR-152 in microglial BV2 cells reduced hernin-induced inflammatory response and reactive oxygen species (ROS) generation, thus protecting co-cultured neuronal HT22 cells. Moreover, overexpression of miR-152 by intracerebroventricular lentivirus injection in ICH rats significantly alleviated neurodecifits, brain edema, and hematoma. These changes were associated with a marked reduction in ICH-induced neuronal death, as detected by co-staining of NeuN and TUNEL, and ICH-induced neuroinflammation, as revealed by inflammatory cytokine levels as well as by the number of Iba1 positive-stained cells in the perihematomal region. Mechanistically, miR-152 significantly inhibited ICH-induced TXNIP expression, and its overexpression blocked the interaction between TXNIP and NOD-like receptor pyrin domain containing 3(NLRP3), thus inhibiting NLRP3-driven inflammasome activation to attenuate neuroinflammation in vivo and in vitro. Moreover, the results of si-TXNIP transfection further confirmed that TXNIP inhibition was involved in the reduction of NLRP3 inflammasome activation by the overexpression of miR-152. Collectively, the present study demonstrates that miR-152 confers protection against ICH-induced neuroinflammation and brain injury by inhibiting TXNIP-mediated NLRP3 inflammasome activation, indicating a potential strategy for ICH treatment.