Department of Medical Science Research Center, Peihua University, Xi'an, 710125, People's Republic of China.
Department of Medical Science Research Center, Shaanxi Fourth People Hospital, Xi'an, 710043, People's Republic of China.
J Neuroinflammation. 2018 Feb 19;15(1):48. doi: 10.1186/s12974-018-1083-y.
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.
创伤性脑损伤（TBI）是全球范围内一个严重的公共卫生和社会经济问题。炎症诱导的继发性损伤是 TBI 的重要发病机制之一。细胞焦亡，一种特定类型的细胞坏死，的分子信号级联反应是 TBI 诱导炎症的关键驱动因素。
在这项研究中，通过基因敲除 caspase-1（caspase-1）的小鼠进行体内控制性皮质撞击损伤，通过 siRNA 敲低和药理学抑制使 caspase-1 缺失的原代神经元受到机械划痕、等张拉伸和 LPS/ATP 的刺激。我们评估了 caspase-1 缺乏对神经功能缺损、炎症因子、组织病理学、细胞凋亡和细胞焦亡的影响。
在体内损伤后急性期（0-48 小时），运动功能障碍、抗炎细胞因子（TGF-β和 IL-10）、促炎细胞因子（IFN-γ、IL-1β和 IL-18）和血乳酸脱氢酶（LDH）以及细胞焦亡相关蛋白（caspase-1、caspase-1 片段、caspase-11 和 GSDMD）增加。TBI 小鼠皮质中 caspase-1 被激活。损伤野生型小鼠的炎症激活比 caspase-1 小鼠更明显。在体外，机械划痕、等张拉伸和 LPS/ATP 诱导神经元细胞焦亡、凋亡、LDH 释放和炎症因子表达增加。通过 siRNA 敲低和药理学抑制抑制 caspase-1 活性可降低机械和炎症应激的影响。
总之，这些数据表明细胞焦亡参与 TBI 后的神经炎症和神经元损伤，caspase-1 的缺失抑制了 TBI 诱导的细胞焦亡。我们的研究结果表明，caspase-1 可能是 TBI 治疗的潜在靶点。
