Dataset Information

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

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.

SUBMITTER: Li S

PROVIDER: S-EPMC8675200 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Li Shanshan S Sun Yiming Y Song Mengmeng M Song Yuting Y Fang Yinquan Y Zhang Qingyu Q Li Xueting X Song Nanshan N Ding Jianhua J Lu Ming M Hu Gang G

JCI insight 20211208 23

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 mic ...[more]

PMID: 34877938

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Project description:Ischemic stroke is a major condition that remains extremely problematic to treat. A cerebral reperfusion injury becomes apparent after an ischemic accident when reoxygenation of the afflicted area produces pathological side effects that are different than those induced by the initial oxygen and nutrient deprivation insult. Pyroptosis is a form of lytic programmed cell death that is distinct from apoptosis, which is initiated by inflammasomes and depends on the activation of Caspase-1. Then, Caspase-1 mobilizes the N-domain of gasdermin D (GSDMD), resulting in the release of cytokines, such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). X-box binding protein l (XBP-1) is activated under endoplasmic reticulum (ER) stress to form an important transcription factor XBP-1 splicing (XBP-1s). The cerebral ischemia/reperfusion (CI/R) causes cytotoxicity, which correlates with the activation of splicing XBP-1 mRNA and NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasomes, along with increases in the expression and secretion of proinflammatory cytokines and upregulation of pyroptosis-related genes in HT22 cells and in the middle cerebral artery occlusion (MCAO) rat model. However, whether XBP-1 plays a role in regulating pyroptosis involved in CI/R is still unknown. Our present study showed that behavior deficits, cerebral ischemic lesions, and neuronal death resulted from CI/R. CI/R increased the mRNA level of XBP-1s, NLRP3, IL-1β, and IL-18 and the expressions of XBP-1s, NLRP3, Caspase-1, GSDMD-N, IL-1β, and IL-18. We further repeated this process in HT22 cells and C8-B4 cells and found that OGD/R decreased cell viability and increased LDH release, XBP-1s, NLRP3, Caspase-1, GSDMD-N, IL-1β, IL-18, and especially the ratio of pyroptosis, which were reversed by Z-YVAD-FMK and downregulated XBP-1. Our results suggest that downregulated XBP-1 inhibited pyroptosis through the classical NLRP3/Caspase-1/GSDMD pathway to protect the neurons.

Project description:Diabetic cardiomyopathy (DCM) is a critical complication of long-term chronic diabetes mellitus, and it is characterized by myocardial fibrosis and myocardial hypertrophy. Previous studies have shown that the pyroptosis pathway was significantly activated in DCM and may be related to the P2X7 receptor. However, the role of the P2X7 receptor in the development of DCM with pyroptosis is still unclear. In this study, we aimed to explore the mechanism of puerarin and whether the P2X7 receptor can be used as a new target for puerarin in the treatment of DCM. We adopted systematic pharmacology and bioinformatic approaches to identify the potential targets of puerarin for treating DCM. Additionally, we employed D-glucose-induced H9C2 rat cardiomyocytes and lipopolysaccharide-treated RAW264.7 mouse mononuclear macrophages as the in vitro model on DCM research, which is close to the pathological conditions. The mRNA expression of cytokines in H9C2 cells and RAW264.7 macrophages was detected. The protein expressions of NLRP3, N-GSDMD, cleaved-caspase-1, and the P2X7 receptor were investigated with Western blot analysis. Furthermore, molecular docking of puerarin and the P2X7 receptor was conducted based on CDOCKER. A total of 348 puerarin targets and 4556 diabetic cardiomyopathy targets were detected, of which 218 were cross targets. We demonstrated that puerarin is effective in enhancing cardiomyocyte viability and improving mitochondrial function. In addition, puerarin is efficacious in blocking NLRP3-Caspase-1-GSDMD-mediated pyroptosis in H9C2 cells and RAW264.7 cells, alleviating cellular inflammation. On the other hand, similar experimental results were obtained by intervention with the P2X7 receptor antagonist A740003, suggesting that the protective effects of puerarin are related to the P2X7 receptor. The molecular docking results indicated key binding activity between the P2X7 receptor and puerarin. These findings indicate that puerarin effectively regulated the pyroptosis signaling pathway during DCM, and this regulation was associated with the P2X7 receptor.

Project description:Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE-/- mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

Dataset Information

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

Publications

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

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