The mechanism of carboxypeptidase E regulating NLRP3 inflammasome signaling in the pathogenesis of depression-like behaviors in mice

OBJECTIVE: Depression is a common mental disease. Carboxypeptidase E (CPE) may be a therapeutic target for depression. This study aims to investigate whether CPE regulates NOD-like receptor protein 3 (NLRP3) inflammasome signaling and affects pyroptosis, thereby improving cellular damage and depression-like behaviors in depressed mice. METHODS: A mouse model of depression-like behavior was established with chronic unpredictable mild stress (CUMS) and treated with Lv-oe-CPE, an NLRP3 inflammasome activator (Nigericin), or an NLRP3 inflammasome inhibitor (MCC950). Anxiety- and depression-like behaviors were assessed through open field test, forced swim test, tail suspension test, and sucrose preference test. Cellular damage in the hippocampal CA1 region was evaluated with H&E and Nissl staining. CPE, gasdermin D-N (GSDMD-N), NLRP3, cleaved Caspase-1, apoptosis-associated spot-like protein (ASC), oxidative stress, interleukin (IL)-1β, and IL-18 levels, and GSDMD-N-positive cells were assessed with western blot, kits, and immunohistochemistry. RESULTS: CPE was down-regulated in the hippocampal CA1 region of CUMS mice, and its re-expression repaired depression-like behaviors. CPE over-expression suppressed NLRP3, cleaved Caspase-1, ASC, IL-1β, and IL-18 levels in the hippocampal CA1 region. NLRP3 inflammasome inactivation alleviated CA1 cellular damage to inhibit depressive-like behaviors, whereas its activation reversed the improving effect of CPE. CPE inactivated NLRP3 inflammasomes, thereby attenuating cell pyroptosis in the hippocampal CA1 region. CONCLUSIONS: CPE is down-regulated in the hippocampal CA1 region of the mouse model of depression-like behavior. CPE over-expression can inhibit NLRP3 inflammasome activation and then reduce pyroptosis, hence repairing cellular damage in the hippocampal CA1 region and eventually suppressing depressive-like behaviors.