NLRP3/caspase-1/GSDMD-mediated pyroptosis exerts a crucial role in astrocyte pathological injury in mouse model of depression.
NLRP3/caspase-1/GSDMD-mediated pyroptosis exerts a crucial role in astrocyte pathological injury in mouse model of depression.
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NLRP3/caspase-1/GSDMD™介导的细胞焦亡在抑郁小鼠模型的星形胶质细胞病理损伤中发挥关键作用
DOI：
10.1172/jci.insight.146852
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发表时间：
2021-12-08
期刊：
影响因子：
8
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Li S;Sun Y;Song M;Song Y;Fang Y;Zhang Q;Li X;Song N;Ding J;Lu M;Hu G
越来越多的证据表明，星形胶质细胞缺失是重度抑郁症（MDD）患者及抑郁小鼠海马体中最重要的病理特征之一。细胞焦亡是一种最近发现的程序性细胞死亡形式，依赖于半胱天冬酶- Gasdermin D（Casp - GSDMD），它与多种神经精神疾病有关。然而，细胞焦亡在MDD发病及神经胶质病理损伤中的作用仍不明确。在此，我们观察到抑郁小鼠出现星形胶质细胞焦亡，这是导致星形胶质细胞缺失的原因，而选择性5 - 羟色胺再摄取抑制剂（SSRI）治疗可减轻慢性温和应激（CMS）模型诱导的细胞焦亡。在小鼠中对GSDMD、Casp - 1以及星形胶质细胞NOD样受体蛋白3（NLRP3）炎症小体进行基因敲除，可缓解类似抑郁的行为，并抑制与细胞焦亡相关的蛋白表达。相反，在海马体中过表达星形胶质细胞GSDMD的N端结构域（GSDMD - N），会消除GSDMD缺陷小鼠行为改变的改善情况。这项研究表明，针对NLRP3 / Casp - 1 / GSDMD介导的细胞焦亡进行干预，可能为抑郁症发病机制中与应激相关的星形胶质细胞缺失提供潜在的治疗益处。
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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影响因子：
7.3
作者：
Martin, Vincent;Riffaud, Armance;Lanfumey, Laurence
通讯作者：
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影响因子：
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DOI：
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影响因子：
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