Increased expression of NLRP3 associate with elevated levels of HMGB1 in children with febrile seizures: a case control study

Abstract

Abstract 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 pro-inflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 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, Capase-1, and pro-inflammatory cytokines of patients with FS. Methods Thirty FS children and thirty age-matched febrile controls were included in this study. Blood was obtained from the FS children within 1 hour of the time of the seizure; subsequently, the content of HMGB1, NLRP3, Capase-1, interleukin (IL)-1β, interleukin (IL)-6, and tumor 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. The Spearman’s rank correlation coefficient was calculated to detect significant correlations between cytokine levels. Results Serum levels of HMGB1, NLRP3, Capase-1, IL-1β, IL-6, and TNF-α were significantly higher in FS patients than febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and Capase-1 (both, p < 0.05). Serum levels of Capase-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 are up-regulated in peripheral serum of FS patients, what may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of Capase-1 was significantly associated with elevated serum levels of and IL-1β. Given that activated Caspase-1 directly regulates the expression of mature IL-1β and positively correlates with activation of NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1β secretion through the activation of NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be the potential target for preventing or limiting FS.