背景:高迁移率族蛋白盒-1(HMGB1)是介导先天性免疫应答激活的内源性危险信号,包括含NLRpyrin结构域3(NLRP3)炎性体激活和促炎细胞因子释放。尽管HMGB1和NLRP3与癫痫的病理生理学有关,HMGB1和NLRP3表达之间的相关性在高热惊厥(FS)儿童中尚未确定。探讨FS患儿细胞外HMGB1与NLRP3的关系,我们分析了FS患者的血清HMGB1,NLRP3,caspase-1和促炎细胞因子。
方法:本研究包括30名FS儿童和30名年龄匹配的发热对照。在癫痫发作后1小时内从FS儿童中获得血液;随后,血清HMGB1、NLRP3、caspase-1、白细胞介素(IL)-1β、用酶联免疫吸附法测定白细胞介素(IL)-6和肿瘤坏死因子-α(TNF-α)。Mann-WhitneyU检验用于比较FS患者和对照组之间的血清细胞因子水平。计算Spearman等级相关系数以检测细胞因子水平之间的显著相关性。
结果:血清HMGB1、NLRP3、caspase-1、IL-1β水平,FS患者的IL-6和TNF-α明显高于发热对照组(p<0.05)。血清HMGB1水平与NLRP3和caspase-1水平显著相关(两者,p<0.05)。血清caspase-1水平与IL-1β水平显著相关(p<0.05)。血清IL-1β水平与IL-6和TNF-α水平显著相关(p<0.05)。
结论:HMGB1在FS患者外周血清中上调,这可能是负责任的,至少在某种程度上,NLRP3和Caspase-1的表达增加。caspase-1表达的增加与血清IL-1β水平的升高显着相关。鉴于活化的Caspase-1直接调节成熟IL-1β的表达并与NLRP3炎性体的活化呈正相关,我们的数据提示,FS患儿外周血HMGB1水平升高可能通过激活NLRP3炎性体介导IL-1β分泌.因此,HMGB1和NLRP3可能是预防或限制FS的潜在靶标.
BACKGROUND: High mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 expression has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, caspase-1, and proinflammatory cytokines in patients with FS.
METHODS: Thirty children with FS and thirty age-matched febrile controls were included in this
study. Blood was obtained from the children with FS within 1 h of the time of the seizure; subsequently, the serum contents of HMGB1, NLRP3, caspase-1, interleukin (IL)-1β, interleukin (IL)-6, and tumour necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann‒Whitney U test was used to compare serum cytokine levels between FS patients and controls. Spearman\'s rank correlation coefficient was calculated to detect significant correlations between cytokine levels.
RESULTS: Serum levels of HMGB1, NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were significantly higher in FS patients than in febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and caspase-1 (both, p < 0.05). Serum levels of caspase-1 were significantly correlated with levels of IL-1β (p < 0.05). Serum levels of IL-1β were significantly correlated with levels of IL-6 and TNF-α (p < 0.05).
CONCLUSIONS: HMGB1 is up-regulated in the peripheral serum of FS patients, which may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of caspase-1 was significantly associated with elevated serum levels of IL-1β. Given that activated Caspase-1 directly regulates the expression of mature IL-1β and positively correlates with activation of the NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1β secretion through the activation of the NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be potential targets for preventing or limiting FS.