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

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),...

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Published in:JCI insight Vol. 6; no. 23
Main Authors: Li, Shanshan, Sun, Yiming, Song, Mengmeng, Song, Yuting, Fang, Yinquan, Zhang, Qingyu, Li, Xueting, Song, Nanshan, Ding, Jianhua, Lu, Ming, Hu, Gang
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 08.12.2021
American Society for Clinical investigation
Subjects:
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
Depression
Inflammation
Psychiatric diseases
Cytokines
ISSN:2379-3708, 2379-3708
Online Access:Get full text
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Summary: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.
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Authorship note: SL and Y Sun contributed equally to this work.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.146852