Neuroimmunomodulation · 2026
The Mechanism of Carboxypeptidase E Regulating NLRP3 Inflammasome Signaling in the Pathogenesis of Depression-Like Behaviors in Mice.
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Yang Xili, Qi Zhimin, Huang Song, Zhao Xinyan, You Yueyang, Liu Huiying, Yu Shuchun, Du Xiaohong, Xiao Fan
Аннотация
INTRODUCTION: Depression is a common mental disease. Carboxypeptidase E (CPE) may be a therapeutic target for depression. This study aimed 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 downregulated in the hippocampal CA1 region of CUMS mice, and its reexpression attenuate depression-like behaviors. CPE overexpression 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 downregulated in the hippocampal CA1 region of the mouse model of depression-like behavior. CPE overexpression can inhibit NLRP3 inflammasome activation and then reduce pyroptosis, hence repairing cellular damage in the hippocampal CA1 region and eventually suppressing depressive-like behaviors.
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 downregulated in the hippocampal CA1 region of CUMS mice, and its reexpression attenuate depression-like behaviors. CPE overexpression 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 downregulated in the hippocampal CA1 region of the mouse model of depression-like behavior. CPE overexpression can inhibit NLRP3 inflammasome activation and then reduce pyroptosis, hence repairing cellular damage in the hippocampal CA1 region and eventually suppressing depressive-like behaviors.