Itaconate inhibits corticosterone-induced necroptosis and neuroinflammation via up-regulating menin in HT22 cells

Abstract

Corticosterone (CORT) damages hippocampus neurons as well as induces neuroin ammation. Tricarboxylic acid cycle metabolite itaconate has an anti-in ammatory role. Necroptosis acts as programmed cell death triggering neuroin ammation. The de ciency of Menin, a multifunctional scaffold protein, aggravates neuroin ammation. In this study, we explored whether itaconate inhibits CORTinduced neuroin ammation 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 in ammatory factors were detected by an enzyme-linked immunosorbent assay kit. Our results showed that CORT increases the contents of pro-in ammatory factors (IL-1β, TNF-α) as well as decreases the contents of anti-in ammatory 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 CORTinduced neuroin ammation 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 neuroin ammation. In brief, these results indicated that itaconate protects HT22 cells against CORT-induced neuroin ammation and necroptosis via upregulating Menin.