Peroxiredoxin 1-mediated activation of TLR4/NF-κB pathway contributes to neuroinflammatory injury in intracerebral hemorrhage
Peroxiredoxin 1-mediated activation of TLR4/NF-κB pathway contributes to neuroinflammatory injury in intracerebral hemorrhage
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DOI：
10.1016/j.intimp.2016.10.025
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发表时间：
2016-12-01
影响因子：
5.6
通讯作者：
Du, Jun-Rong
中科院分区：
文献类型：
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作者：
Liu, Dong-Ling;Zhao, Li-Xue;Du, Jun-Rong
细胞外过氧化物还毒素（Prxs）通过诱导toll样受体4 （TLR4）激活的促炎特性在多种应激条件下逐渐被揭示，包括脑缺血但不包括出血。Prxl被认为是脑出血（ICH）急性和亚急性期Prxs的主要出血应激诱导亚型。然而，Prxl在脑出血后神经炎症损伤中的潜在作用尚不清楚。本研究探讨细胞外Prxl在培养小鼠巨噬细胞和胶原酶诱导小鼠脑出血模型中的促炎作用及其机制。目前的研究结果表明，外源性Prx1 （0-50 nM）与小鼠RAW264.7巨噬细胞孵育可导致TLR4的表达增加，核因子KB (NF-kappa B) p65的核易位以及促炎介质（NO， TNF-a和IL-6）的产生呈浓度依赖性。此外，脑出血后72小时内还会引起小鼠神经功能缺损、脑水肿和神经病理改变，如神经元损伤、星形胶质细胞和小胶质/巨噬细胞活化、中性粒细胞和T淋巴细胞侵袭。此外，ICH刺激Prxl的表达和细胞外释放，TLR4/NF-kappa B信号激活，反映在TLR4表达增加，细胞外信号调节激酶（ERIC） 1/2和NF-kappa B激活，以及细胞因子（tnf - 0:， IL-6和IL-17）的产生。综上所述，这些发现表明细胞外prx1介导的TLR4/NF-kappa B通路激活可能导致脑出血后神经炎症损伤，因此阻断Prx1-TLR4信号通路可能为出血性卒中提供一种新的抗神经炎症策略，延长了治疗窗口期。(C) 2016 Elsevier B.V.版权所有
The proinflammatory properties of extracellular peroxiredoxins (Prxs) via induction of Toll-like receptor 4 (TLR4) activation have been gradually revealed under diverse stress conditions, including cerebral ischemia but not hemorrhage. Prxl is proposed to be a major hemorrhagic stress-inducible isoform of Prxs during acute and subacute phases of intracerebral hemorrhage (ICH). However, the potential of Prxl in the neuroinflammatory injury after ICH remains unclear. This study investigated the proinflammatory effect and underlying mechanism of extracellular Prxl in cultured murine macrophages and a collagenase-induced mouse ICH model. The current results show that incubation of exogenous Prx1 (0-50 nM) with murine RAW264.7 macrophages resulted in increased expression of TLR4, nuclear translocation of nuclear factor KB (NF-kappa B) p65 and production of proinflammatory mediators (NO, TNF-a and IL-6) in a concentration-dependent manner. In addition, ICH induced murine neurological deficits, cerebral edema and neuropathological alterations, such as neuron injury, astrocyte and microglia/macrophage activation, and neutrophil and T lymphocyte invasion up to 72 h after ICH. Moreover, ICH stimulated Prxl expression and extracellular release, TLR4/NF-kappa B signaling activation, reflected by increases in TLR4 expression, extracellular signal-regulated kinase (ERIC) 1/2 and NF-kappa B activation, and production of cytokines (TNF-o:, IL-6 and IL-17). Taken together, these findings suggest that extracellular Prxl-mediated TLR4/NF-kappa B pathway activation probably contributes to neuroinflammatory injury after ICH, and thus blocking Prx1-TLR4 signaling might provide a novel anti-neuroinflammatory strategy with extended therapeutic window for hemorrhagic stroke. (C) 2016 Elsevier B.V. All rights reserved.