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

2019 unpublished
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.
more » ... 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. of neurons, thereby promoting the development of epilepsy [4-6]. However, the mechanism of glial cell activation is complex and has not been fully explored [6]. Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily[7]. It is involved in a variety of biological effects, including cell proliferation, differentiation, migration, apoptosis and necrosis, and induction of inflammatory cytokine expression [7, 8]. The main receptor for TWEAK is Fn14, a fibroblast growth factor inducible 14 kDa protein, and the main source of TWEAK protein are monocyte/macrophage family cells, including microglia [9]. Soluble TWEAK can modulate the expression of proteins that are involved in inflammation and opening of the blood brain barrier [9]. In murine and human astrocytes, the TWEAK/Fn14 pathway stimulates reactivity when cell proliferation is activated and inflammatory factors are produced [10]. TWEAK/Fn14 pathway is involved in human neurodegenerative disease. Anti-TWEAK antibodies can improve a murine model of parkinson's disease [11]. LncRNA is a class of non-coding RNAs greater than 200 nucleotides in length. LC designed and analyzed the experiment, and was a major contributor in writing the manuscript. RS, XZ, CH, XHZ, LC, RY and RL performed the experiment. All authors read and approved the final manuscript.
doi:10.21203/rs.2.19453/v1 fatcat:y5akm7mnqbfr5etfb7nvaosni4