USP2 regulates neuroinflammation to ameliorate depression via the IL-1R2/NF-κB signalling pathway

Abstract

Background Ubiquitin-specific proteases (USPs) play a vital role in the modulation of protein trafficking and degradation through deubiquitination. It was reported that there is a strong correlation of ubiquitin-specific protease 2 (USP2) expression with apoptosis and inflammation. Nonetheless, the role of USP2 in alleviating depression remains unclear, and no therapeutic strategies targeting USP2 to treat depression have been reported. Methods The forced swim test (FST) and tail suspension test (TST) were performed to investigate depressive-like behaviour. Western blotting was used to examine the expression levels of proteins related to neuroinflammation. A lentivirus carrying USP2 shRNA (LV-shUSP2) was utilized to inhibit USP2 function/expression. The small-molecule USP2 inhibitor ML364 was used to suppress USP2 activity. A USP2-overexpressing lentivirus (LV-USP2) was utilized to promote USP2 function/expression. Additionally, the role of USP2 in corticosterone (CORT)-induced depression in mice was confirmed using HT-22 cells. Results The expression of USP2 in the hippocampus was significantly decreased in CORT-induced depression model mice. Similar to CORT, LV-shUSP2 and ML364 caused depressive-like behaviour in mice. In CORT-treated mice, both LV-USP2 and the antidepressant venlafaxine (VNX) exerted antidepressant-like effects and ameliorated the downregulation of USP2 in the hippocampus. In addition, VNX reversed the induction of depressive-like behaviour in mice caused by LV-shUSP2 or ML364 and positively modulated USP2 in the hippocampus. In-depth mechanistic studies showed that CORT, LV-shUSP2 and ML364 all reduced IL-1 receptor type 2 (IL-1R2) expression and activated nuclear factor κB (NF-κB) signalling in the hippocampus. However, both VNX and LV-USP2 suppressed the downregulation of IL-1R2 and decreased the activation of NF-κB signalling. In HT22 cells, VNX-induced upregulation of UPS2 or LV-USP2 could regulate neuroinflammation to ameliorate neuronal damage via the IL-1R2/NF-κB signalling pathway. Conclusions Our data suggest that USP2 exerts antidepressant-like effects on hippocampal neurons and that VNX is a novel therapeutic agent that can positively regulate USP2 to ameliorate depression. Additionally, the USP2-mediated IL-1R2/NF-κB pathway may be a potential target for the treatment of depression, allowing the development of more efficient antidepressant agents.