Journal Article

NLRP3/caspase-1/GSDMD–mediated pyroptosis exerts a crucial role in astrocyte pathological injury in mouse model of depression

Hu, Gang, Zhang, Qingyu, Sun, Yiming, Song, Yuting, Song, Mengmeng, Li, Xueting, Lu, Ming, Li, Shanshan, Fang, Yinquan, Song, Nanshan, Ding, Jianhua

2021

Overview

Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and depressive mice. Pyroptosis is a recently discovered form of programmed cell death depending on Caspase–gasdermin D (Casp-GSDMD), which is involved in multiple neuropsychiatric diseases. However, the involvement of pyroptosis in the onset of MDD and glial pathological injury remains obscure. Here, we observed that depressive mice showed astrocytic pyroptosis, which was responsible for astrocyte loss, and selective serotonin reuptake inhibitor (SSRI) treatment could attenuate the pyroptosis induced by the chronic mild stress (CMS) model. Genetic KO of GSDMD, Casp-1, and astrocytic NOD-like receptor protein 3 (NLRP3) inflammasome in mice alleviated depression-like behaviors and inhibited the pyroptosis-associated protein expression. In contrast, overexpression of astrocytic GSDMD–N-terminal domain (GSDMD-N) in the hippocampus could abolish the improvement of behavioral alterations in GSDMD-deficient mice. This work illustrates that targeting the NLRP3/Casp-1/GSDMD–mediated pyroptosis may provide potential therapeutic benefits to stress-related astrocyte loss in the pathogenesis of depression.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Animals / Apoptosis / Astrocytes - metabolism / Behavior / Caspase 1 - metabolism / Caspase-1 / Cell death / Depression - genetics / Disease / Disease Models, Animal / Hippocampus / Humans / Inflammasomes / Inflammation / Mental depression / Mental disorders / Mice / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Pathogenesis / Proteins / Pyroptosis / Pyroptosis - immunology / Serotonin uptake inhibitors / Signal transduction