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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Veröffentlicht in:	JCI insight Jg. 6; H. 23
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 08.12.2021 American Society for Clinical investigation
Schlagworte:	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
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Abstract	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.
AbstractList	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.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. 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.
Author	Hu, Gang Zhang, Qingyu Sun, Yiming Song, Yuting Song, Mengmeng Li, Xueting Lu, Ming Li, Shanshan Fang, Yinquan Song, Nanshan Ding, Jianhua
AuthorAffiliation	2 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, and 1 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China 3 Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
AuthorAffiliation_xml	– name: 2 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, and – name: 1 Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China – name: 3 Neuroprotective Drug Discovery Key Laboratory, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Author_xml	– sequence: 1 givenname: Shanshan surname: Li fullname: Li, Shanshan – sequence: 2 givenname: Yiming surname: Sun fullname: Sun, Yiming – sequence: 3 givenname: Mengmeng surname: Song fullname: Song, Mengmeng – sequence: 4 givenname: Yuting surname: Song fullname: Song, Yuting – sequence: 5 givenname: Yinquan surname: Fang fullname: Fang, Yinquan – sequence: 6 givenname: Qingyu surname: Zhang fullname: Zhang, Qingyu – sequence: 7 givenname: Xueting surname: Li fullname: Li, Xueting – sequence: 8 givenname: Nanshan surname: Song fullname: Song, Nanshan – sequence: 9 givenname: Jianhua surname: Ding fullname: Ding, Jianhua – sequence: 10 givenname: Ming surname: Lu fullname: Lu, Ming – sequence: 11 givenname: Gang surname: Hu fullname: Hu, Gang
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/34877938$$D View this record in MEDLINE/PubMed
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Keywords	Depression Inflammation Psychiatric diseases Cytokines
Language	English
License	http://creativecommons.org/licenses/by/4.0 This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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SubjectTerms	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
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Title	NLRP3/caspase-1/GSDMD–mediated pyroptosis exerts a crucial role in astrocyte pathological injury in mouse model of depression
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