Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo.
Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo.
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DOI：
10.1186/s12974-018-1083-y
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发表时间：
2018-02-19
影响因子：
9.3
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Liu W;Chen Y;Meng J;Wu M;Bi F;Chang C;Li H;Zhang L
创伤性脑损伤是世界范围内严重的公共卫生和社会经济问题。炎症继发性损伤是颅脑损伤的重要致病参数之一。上睑下垂是一种特殊类型的细胞坏死，其分子信号级联是脑外伤引起炎症的关键驱动因素。本研究采用Caspase-1基因敲除的小鼠(Caspase-1−/−)，在体内造成可控性皮质撞击损伤，并用机械划痕、等轴拉伸和脂多糖/三磷酸腺苷体外刺激原代Caspase-1缺失神经元。我们评估了caspase-1缺陷对神经功能缺陷、炎症因子、组织病理学、细胞凋亡和下垂的影响。在体内急性损伤后(0~48h)，运动缺陷、抗炎细胞因子(转化生长因子-β和IL-10)、促炎细胞因子(干扰素-γ、IL-1β和IL-18)、血乳酸脱氢酶(LDH)以及与上睑下垂相关的蛋白(caspase-1、caspase-1片段、caspase-11和GSDMD)均增加。脑损伤小鼠大脑皮层caspase-1被激活。与caspase-1−/−小鼠相比，受损伤的野生型小鼠的炎症激活程度更深。在体外，机械划痕、等轴拉伸和内毒素/三磷酸腺苷诱导的神经元下垂、细胞凋亡、乳酸脱氢酶释放、炎性因子表达增加。通过siRNA敲除和药物抑制抑制caspase-1活性，减轻机械应激和炎症应激的影响。综上所述，这些数据表明，上睑下垂参与了脑外伤后的神经炎症和神经元损伤，而caspase-1的消融可抑制脑损伤后引起的下垂。我们的研究结果表明，caspase-1可能是脑外伤治疗的潜在靶点。本文的在线版本(10.1186/s12974-0181083-y)包含向授权用户提供的补充材料。
Traumatic brain injury (TBI) is a critical public health and socioeconomic problem throughout the world. Inflammation-induced secondary injury is one of the vital pathogenic parameters of TBI. Molecular signaling cascades of pyroptosis, a specific type of cellular necrosis, are key drivers of TBI-induced inflammation. In this study, mice with genetically ablated caspase-1 (caspase-1−/−) were subjected to controlled cortical impact injury in vivo, and primary neuron deficient in caspase-1 through siRNA knockdown and pharmacologic inhibition was stimulated by mechanical scratch, equiaxial stretch, and LPS/ATP in vitro. We evaluated the effects of caspase-1 deficiency on neurological deficits, inflammatory factors, histopathology, cell apoptosis, and pyroptosis. During the acute post-injury period (0–48 h) in vivo, motor deficits, anti-inflammatory cytokines (TGF-β and IL-10), pro-inflammatory cytokines (IFN-γ, IL-1β, and IL-18), and blood lactate dehydrogenase (LDH), as well as pyroptosis-related proteins (caspase-1, caspase-1 fragments, caspase-11 and GSDMD), were increased. Caspase-1 was activated in the cortex of TBI mice. Inflammatory activation was more profound in injured wild-type mice than in caspase-1−/− mice. In vitro, mechanical scratch, equiaxial stretch, and LPS/ATP-induced neuron pyroptosis, apoptosis, LDH release, and increased expression of inflammatory factors. The effects of mechanical and inflammatory stress were reduced through inhibition of caspase-1 activity through siRNA knockdown and pharmacologic inhibition. Collectively, these data demonstrate that pyroptosis is involved in neuroinflammation and neuronal injury after TBI, and ablation of caspase-1 inhibits TBI-induced pyroptosis. Our findings suggest that caspase-1 may be a potential target for TBI therapy. The online version of this article (10.1186/s12974-018-1083-y) contains supplementary material, which is available to authorized users.
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影响因子：
5.6
作者：
Irrera N;Pizzino G;Calò M;Pallio G;Mannino F;Famà F;Arcoraci V;Fodale V;David A;Francesca C;Minutoli L;Mazzon E;Bramanti P;Squadrito F;Altavilla D;Bitto A
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影响因子：
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作者：
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Price JV
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作者：
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通讯作者：
Flavell, Richard A.
影响因子：
6.3
作者：
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Dietrich, W. Dalton