Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation
Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia/macrophage and suppressing NF-κB activation
复制标题
Caspase-1 抑制通过极化 M2 小胶质细胞/巨噬细胞和抑制 NF-κ B 激活介导实验性卒中的神经保护
DOI：
10.1016/j.bbrc.2019.03.202
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发表时间：
2019-05-28
影响因子：
3.1
通讯作者：
Wang, Lihua
中科院分区：
文献类型：
--
作者：
Li, Qian;Dai, Zhenguo;Wang, Lihua
中风是一种危及生命的神经系统疾病，治疗选择有限。炎症被认为参与了缺血性中风的发病机制，并对脑损伤的程度做出了贡献。VX-765是一种有效的、选择性的小分子caspase-1抑制剂。目前的研究表明，VX-765在多种疾病中具有抗炎作用；然而，VX-765对缺血性卒中的影响尚不清楚。在本研究中，我们确定了VX-765对小鼠大脑中动脉短暂性阻塞(MCAO)的神经保护作用。我们发现，通过给予VX-765抑制caspase-1可以通过减少脑梗塞体积和改善神经功能缺失来改善小鼠缺血性卒中后的脑损伤。从机制上讲，我们发现VX-765在缺血性损伤中的作用可能与减少小胶质细胞的激活，下调相关的促炎细胞因子的产生，包括IL-1β，TNF-α和iNOS，以及上调抗炎细胞因子如转化生长因子-1β和ym-1有关。此外，VX-765通过将小胶质细胞极化转变为M2表型来改变小胶质细胞的表型，这显然与抑制核因子-kappaB的激活有关。我们的发现表明，VX-765主要通过将小胶质细胞极化从M1表型转变为M2表型来保护MCAO损伤和减轻小胶质细胞介导的神经炎症。VX-765可能是一种潜在的改善缺血性卒中的治疗药物。(C)2019 Elsevier Inc.保留所有权利。
Stroke is a life-threatening neurological disease with limited therapeutic options. Inflammation is believed to be involved in the pathogenesis of ischemic stroke and contribute to the degree of brain injury. Vx-765 is a potent, selective, small-molecule caspase-1 inhibitor. Current studies have shown the anti-inflammatory properties of vx-765 in various disease; however, the impact of vx-765 on the ischemic stroke is still unclear. In the present study, we determine the neuroprotective effect of vx-765 in mice subjected to transient middle cerebral artery occlusion (MCAO). We found that caspase-1 inhibition by administration of vx-765 ameliorated cerebral injury in mice after ischemic stroke by reducing infarct volume and ameliorating the neurological deficits. Mechanistically, we showed that the contribution of vx-765 to ischemic injuries may be associated with reducing microglial activation, and downregulating the production of associated pro inflammatory cytokines including IL-1 beta, TNF-alpha, and iNOS, as well as upregulating anti-inflammatory cytokines such as TGF-1 beta and YM-1. Additionally, vx-765 altered the phenotype of microglia via switching the microglia polarization toward M2 phenotype, as demonstrably related to inhibition of the NF-kappa B activation. Our findings indicate that vx-765 protects against MCAO injury and attenuated microglia mediated neuroinflammation primarily by shifting microglia polarization from M1 phenotype toward M2 phenotype. Vx-765 might be a potential therapeutic drug for ameliorating ischemic stroke. (C) 2019 Elsevier Inc. All rights reserved.