A novel Tweak/ Stat1/ Snhg3 positive feedback circuit contributes to the glial cell activation in temporal lobe epilepsy mice

Gliosis is an important feature of temporal lobe epilepsy (TLE), but the regulatory mechanism of glial cell activation remains unclear. Small nucleolar RNA host gene 3 (Snhg3) has been reported to be involved in cell proliferation and migration in various cancers. However, its role in the development of TLE has been hardly explored. Here, we established a mouse TLE model by injecting intraperitoneally with pilocarpine, and found that Tweak expression was significantly induced in TLE mice. Inhibiting Tweak expression by the injection of siRNA notably rescued the glial cell activation, neuroinflammatory cytokine secretion and cognitive behavior disorder in TLE mice. Molecular mechanism studies showed that cell proliferation, migration, inflammatory factor secretion, Stat1 pathway activation and Snhg3 expression were promoted after we incubated Tweak recombinant protein (rTweak) with mouse astrocytes (MAs). The Tweak neutralizing antibody (anti-Tweak) showed the opposite effect to that of rTweak. In subsequent researches, we found that Stat1 directly bound to Snhg3 promoter and they elevated the expression of each other. Moreover, both of them boosted cell proliferation, migration, inflammatory factor secretion and Tweak expression. Thus, we found a feedback regulation loop consisting of Tweak/Fn14, Stat1/ p-Stat1 and Snhg3 in the MAs, which increased cell activation. In vivo experiment demonstrated that the reduction of Snhg3 inhibited glial cell activation induced by TLE, and Tweak/Stat1/Snhg3 feedback circuit also existed in TLE mice. In short, our research testified a feedback regulation loop consisting of Tweak/Stat1/Snhg3, which was involved in the activation of hippocampal glial cells in TLE mice.