Chronic cerebral hypoperfusion activates AIM2 and NLRP3 inflammasome
Chronic cerebral hypoperfusion activates AIM2 and NLRP3 inflammasome
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DOI：
10.1016/j.brainres.2020.146779
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发表时间：
2020-06-01
期刊：
影响因子：
2.9
通讯作者：
Tomimoto, Hidekazu
中科院分区：
文献类型：
--
作者：
Matsuyama, Hirofumi;Shindo, Akihiro;Tomimoto, Hidekazu
炎症在急慢性脑缺血中起重要作用。最近的报道表明，由组织损伤引发的炎症反应是由一种称为炎性体的多蛋白复合物介导的。nod样受体家族，pyrin结构域3 （NLRP3）和黑色素瘤2 （AIM2）炎性体复合物缺失触发caspase 1介导的白介素(IL)-1 β和IL-18成熟。这项研究验证了慢性脑灌注不足激活脑白质中的炎性小体的假设。采用内径0.18 mm的微线圈对C57BL/6J小鼠进行假颈总动脉狭窄或双侧颈总动脉狭窄（BCAS）手术，诱导脑灌注不足。在BCAS后2周和4周处死小鼠（每组n = 5）。冠状切片染色抗nlrp3和抗aim2抗体。使用免疫组织化学和细胞计数评估炎症小体和细胞因子的激活。ELISA法检测各组IL-18、IL-1 β水平。细胞计数显示，在BCAS后2周和4周，NLRP3和AIM2炎症小体增加。脑白质和胼胝体的神经胶质细胞具有免疫反应性。与假手术组比较，IL-18、IL-1 β浓度显著升高。脑梗死患者尸检后脑内神经胶质细胞中NLRP3和AIM2的表达在慢性期上调。这些结果表明，慢性脑灌注不足可诱导NLRP3和AIM2炎性小体的上调；因此，炎症小体可能在慢性脑灌注不足时星形胶质细胞和小胶质细胞的无菌炎症反应中发挥重要作用。
Inflammation plays an important role in acute and chronic cerebral ischemia. Recent reports indicate that the inflammatory response triggered by tissue damage is mediated by a multiple-protein complex called the inflammasome. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasome complex triggers caspase 1-mediated maturation of interleukin (IL)-1 beta and IL-18. This study tested the hypothesis that chronic cerebral hypoperfusion activates inflammasomes in the white matter of the brain. To induce cerebral hypoperfusion, C57BL/6J mice were subjected to a sham or bilateral common carotid artery stenosis (BCAS) operation using microcoils with an internal diameter of 0.18 mm. At 2 and 4 weeks after BCAS, the mice were sacrificed (n = 5 in each group). Coronal sections were stained with anti-NLRP3 and anti-AIM2 antibodies. Activation of the inflammasome and cytokines was assessed using immunohistochemistry and cell counting. IL-18 and IL-1 beta levels were determined by ELISA. Cell counting revealed an increase in NLRP3 and AIM2 inflammasomes at 2 and 4 weeks after BCAS. Immunoreactivity was observed in glial cells in the white matter and corpus callosum. IL-18 and IL-1 beta concentrations were significantly increased compared with those in the sham operation group. Expression of NLRP3 and AIM2 was upregulated in glial cells in the autopsied brains of patients with cerebral infarction in the chronic phase. These results suggest that chronic cerebral hypoperfusion induces upregulation of NLRP3 and AIM2 inflammasomes; therefore, inflammasomes may play an important role in the sterile inflammatory response in astrocytes and microglia during chronic cerebral hypoperfusion.