Pro-inflammatory role of high-mobility group box-1 on brain mast cells via the RAGE/NF-κB pathway.

High-mobility group box-1 (HMGB-1) acts as a pro-inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro-inflammatory effects of HMGB-1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB-1 and explored whether this process is involved in the pro-inflammatory effects of HMGB-1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB-1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague-Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB-1. Increased levels of tumor necrosis factor and IL-1β were observed in the P815 cells, as well as in the rats' brains, after HMGB-1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)-siRNA inhibited the HMGB-1-induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor-κB (NF-κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB-1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood-brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB-1-induced pro-inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro-inflammatory effect of HMGB-1 on the CNS, probably via activating the RAGE/NF-κB pathway.