Meng Xian-Fang, Wang Xiao-Lan, Tian Xiu-Juan, Yang Zhi-Hua, Chu Guang-Pin, Zhang Jing, Li Man, Shi Jing, Zhang Chun
Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Mol Neurobiol. 2014 Apr;49(2):673-84. doi: 10.1007/s12035-013-8551-2. Epub 2013 Sep 8.
Diabetic encephalopathy is one of the most common complications of diabetes. Inflammatory events during diabetes may be an important mechanism of diabetic encephalopathy. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein (ASC), and caspase 1 or 5, which functions to switch on the inflammatory process and the release of inflammatory factors. The present study hypothesized that the formation and activation of NLRP1 inflammasome turns on neuroinflammation and neuron injury during hyperglycemia. The results demonstrated that the levels of interleukin-1 beta (IL-1β) were increased in the cortex of streptozocin (STZ)-induced diabetic rats. The levels of mature IL-1β and IL-18 were also elevated in culture medium of neurons treated with high glucose (50 mM). The expression of three essential components of the NLRP1 inflammasome complex, namely, NLRP1, ASC, and caspase 1, was also upregulated in vivo and in vitro under high glucose. Silencing the ASC gene prevented the caspase-1 activation, and inhibiting caspase 1 activity blocked hyperglycemia-induced release of inflammatory factors and neuron injury. Moreover, we found that pannexin 1 mediated the actvitation of NLRP1 inflammasome under high glucose. These results suggest that hyperglycemia induces neuroinflammation through activation of NLRP1 inflammasome, which represents a novel mechanism of diabetes-associated neuron injury.
糖尿病性脑病是糖尿病最常见的并发症之一。糖尿病期间的炎症事件可能是糖尿病性脑病的重要机制。炎性小体是一种多蛋白复合物，由NOD样受体蛋白（NLRP）、凋亡相关斑点样蛋白（ASC）和半胱天冬酶1或5组成，其功能是开启炎症过程并释放炎性因子。本研究假设，高血糖期间NLRP1炎性小体的形成和激活会引发神经炎症和神经元损伤。结果表明，链脲佐菌素（STZ）诱导的糖尿病大鼠皮层中白细胞介素-1β（IL-1β）水平升高。用高糖（50 mM）处理的神经元培养基中成熟IL-1β和IL-18水平也升高。在高糖条件下，体内和体外NLRP1炎性小体复合物的三个关键成分，即NLRP1、ASC和半胱天冬酶1的表达也上调。沉默ASC基因可防止半胱天冬酶-1激活，抑制半胱天冬酶1活性可阻断高血糖诱导的炎性因子释放和神经元损伤。此外，我们发现泛连接蛋白1在高糖条件下介导NLRP1炎性小体的激活。这些结果表明，高血糖通过激活NLRP1炎性小体诱导神经炎症，这代表了糖尿病相关神经元损伤的一种新机制。
