HIF-1α/BNIP3L induced cognitive deficits in a mouse model of sepsis-associated encephalopathy

Zhao, Lina; Song, Yu; Zhang, Ying; Liu, Haiying; Shen, Yiming; Yang, Fan; Li, Yun; Xie, Keliang

doi:10.3389/fimmu.2022.1095427

Cited by 11 publications

(5 citation statements)

References 31 publications

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“…In addition to nuclear autophagy, mitochondrial damage is also observed in SAE, which manifests as a shorter and smaller mitochondria with a disrupted membrane structure [ 4 , 35 , 36 , 37 , 38 ]. Mitochondrial damage in SAE can trigger the production of reactive oxygen species (ROS) and activation of inflammatory pathways, ultimately leading to neuronal cell death and brain dysfunction [ 39 , 40 ].…”

Section: Introductionmentioning

confidence: 99%

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Xie

Bai

et al. 2023

Brain Sciences

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Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which is a life-threatening condition resulting from a dysregulated host response to infection. Pyroptosis, a pro-inflammatory mode of lytic cell death mediated by GSDMD (Gasdermin D), is involved in the pathogenesis of SAE. While autophagy has been extensively studied in SAE, the role of nuclear autophagy is not yet well understood. In this study, we aimed to investigate the involvement of pyroptosis and neural nuclear autophagy in the pathogenesis of SAE. We analyzed a CLP (cecal ligation and puncture)-induced SAE model in wild-type and GSDMD−/− mice to gain insights into the underlying mechanisms. Here, we show that in sepsis, neural nuclear autophagy is extremely activated, and nuclear LaminB decreases and is accompanied by an increase in the ratio of LC3BII/I. These effects can be reversed in GSDMD−/− mice. The behavioral outcomes of septic wild-type mice are impaired by the evidence from the novel object recognition test (NORT) and open field test (OFT), but are improved in septic GSDMD−/− mice. In conclusion, our study demonstrates the activation of neural nuclear autophagy in SAE. The absence of GSDMD inhibits nuclear autophagy and improves the behavioral outcomes of SAE.

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Section: Introductionmentioning

confidence: 99%

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Xie

Bai

et al. 2023

Brain Sciences

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“…We unequivocally demonstrate that activated GSDMD acts as an upstream factor, causing Drp1 activation, neuronal damage, synaptic abnormalities, and altered neural oscillations in SAE mice. This cascade of events is effectively reversed by treatment with NSA or Mdivi-1, suggesting that activated GSDMD may promote the translocation of Drp1 to the mitochondrial membrane, subsequently provoking mitochondrial dysfunctions [11,47,48].…”

Section: Discussionmentioning

confidence: 99%

GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy

Fu,

Zhang,

Shi

et al. 2024

J Neuroinflammation

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Background Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. Methods C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. Results CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. Conclusions Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

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“…As inhibitors of HIF are now commercially available [25][26][27], future studies using either these inhibitors or experiments with HIF-1α-deficient knockout animals are needed to draw such conclusions. Yet, we know from sepsis models that HIF-1α is a critical determinant of the sepsis phenotype, promoting the production of many inflammatory cytokines (e.g., TNFα, IL-1, IL-4, IL-6 and IL12), and HIF-1α deletion in human macrophages reduces LPSinduced mortality and alleviates the clinical presentation of sepsis, including hypotension and hypothermia [12,28]. Bacterial infections or sterile cytokine storms have been described to play a pivotal role in ACLF pathogenesis [22,29].…”

Section: Discussionmentioning

confidence: 99%

The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure

Mücke,

El Bali,

Schwarzkopf

et al. 2024

IJMS

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Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1α) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1α in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1α expression and the intracellular pathway of HIF-1α induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1α expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1α in human liver tissue. Intrahepatic HIF-1α expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1α was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1α expression was not elevated. In human liver tissue samples, HIF-1α expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1α expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.

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HIF-1α/BNIP3L induced cognitive deficits in a mouse model of sepsis-associated encephalopathy

Cited by 11 publications

References 31 publications

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy

The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure

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