Itaconate Inhibits Corticosterone-Induced Necroptosis and Neuroinflammation via Up-regulating Menin in HT22 Cells

Abstract

Abstract Corticosterone (CORT) damages hippocampus neurons as well as induces neuroinflammation. Tricarboxylic acid cycle metabolite itaconate has an anti-inflammatory role. Necroptosis acts as programmed cell death triggering neuroinflammation. The deficiency of Menin, a multifunctional scaffold protein, aggravates neuroinflammation. In this study, we explored whether itaconate inhibits CORT-induced neuroinflammation and necroptosis as well as the mediatory role of Menin in this protective effect of itaconate using an exposure of CORT to HT22 hippocampal neuronal cells. The viability of HT22 cells was examined by the Cell Counting Kit 8 (CCK-8). The morphology of HT22 cells was observed by transmission electron microscope (TEM). The expressions of necroptosis-related proteins (p-RIP1/ RIP1, p-RIP3/ RIP3, and p-MLKL/ MLKL) were evaluated by Western blotting. The contents of inflammatory factors were detected by an enzyme-linked immunosorbent assay kit. Our results showed that CORT increases the contents of pro-inflammatory factors (IL-1β, TNF-α) as well as decreases the contents of anti-inflammatory factors (IL4, IL10) in HT22 cells. We also found that CORT increases the expressions of necroptosis-related proteins (p-RIP1/ RIP1, p-RIP3/ RIP3, and p-MLKL/ MLKL) and decreases the cell viability in HT22 cells, indicating that CORT induces necroptosis to HT22 cells. Itaconate improves CORT-induced neuroinflammation and necroptosis. Furthermore, itaconate upregulates the expression of Menin in CORT-exposed HT22 cells. Importantly, silencing Menin abolishes the antagonistic effect of itaconate on CORT-induced necroptosis and neuroinflammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroinflammation and necroptosis via upregulating Menin.