Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors

Sun, Zhao-Wei; Wang, Xue; Zhao, Yun; Sun, Zhao-Xin; Wu, Yu-Han; Hu, Hui; Zhang, Ling; Wang, Shi-Da; Li, Feng; Wei, Ai-Jun; Feng, Hong; Xie, Fang; Qian, Ling-Jia

doi:10.1016/j.bbi.2023.10.010

Cited by 22 publications

(8 citation statements)

References 41 publications

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“…Cldn5 overexpression and EZH2 KD block the stress-induced aggregation of TNF-α in the HPC and attenuate depression-like phenotypes. Moreover, 5 mg/kg/day of fluoxetine normalized Cldn5 activation in vivo and inhibited TNF-α elevation in the blood and HPC of chronically stressed mice [125]. Together, these findings suggest that chronic-stress-induced BBB breakdown allows for the diffusion of TNF-α into the HPC, leading to the development of depression.…”

Section: Tnf-αmentioning

confidence: 73%

“…The administration of a traditional medicine agent, Rannasangpei (RSNP), or the active ingredient crocin-1 following UCMS reduced TNF-α mRNA expression in the PFC and HPC. The reason underlying the brain-specific changes of TNF-α remains unknown but is supported by a previous study that measured the exercise-induced reduction of TNF-α in the HPC but not the PFC, though other brain regions such as the HPC and the lateral habenula are also sensitive to increased TNF-α [36,125]. Accumulating data support the sensitivity of the PFC to the detrimental effects of stress exposure [15,118,132].…”

Section: Tnf-αmentioning

confidence: 89%

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Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

White,

Elias,

Orozco

et al. 2024

IJMS

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The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress—a relationship that is continually being defined. Many studies investigating the effects of chronic stress on neuroinflammation in rodent models have identified significant changes in inflammatory modulators, including nuclear factor-κB (NF-κB) and toll-like receptors (TLRs), and cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6. This suggests that these are key inflammatory factors in the chronic stress response, which may contribute to the establishment of anxiety and depression-like symptoms. The behavioral and neurological effects of modulating inflammatory factors through gene knockdown (KD) and knockout (KO), and conventional and alternative medicine approaches, are discussed.

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Section: Tnf-αmentioning

confidence: 73%

Section: Tnf-αmentioning

confidence: 89%

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

White,

Elias,

Orozco

et al. 2024

IJMS

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“…The relationship between inflammation and depression has garnered significant attention, with cumulative evidence suggesting that inflammatory processes play a crucial role in the initiation and development of depression. Our team’s previous research demonstrated that injection of TNF-α into the hippocampus evoked depression-like behaviors [ 28 ]. Besides, the facilitative role of brain IL-1β in the pathogenesis of depression has also been revealed [ 71 , 72 ], confirming the contribution of central inflammatory cytokines in depression.…”

Section: Discussionmentioning

confidence: 99%

“…For immunohistofluorescence, the brains were separated and post-fixed in 4% paraformaldehyde (PFA) at 4°C overnight and immersed in 20% sucrose (4% PFA as solvent) followed by 30% sucrose (in 0.1 M PBS). The brain samples were cut into 20-µm-thick sections using a Leica CM1950 cryostat and subjected to immunohistofluorescence following routine protocols as described previously [ 28 ]. The antibodies used were provided in Supplementary Table 2 .…”

Section: Methodsmentioning

confidence: 99%

GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice

Wang,

Wu,

Tian

et al. 2024

Cell Biosci

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Background Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear. Methods The chronic stress mouse model was utilized to explore the relationship between microglial activation and spatial memory impairment. The effect of hippocampal hyperglycemia on microglial activation was evaluated through hippocampal glucose-infusion and the incubation of BV2 cells with high glucose. The gain-and loss-of-function experiments were conducted to investigate the role of GLUT1 in microglial proinflammatory activation. An adeno-associated virus (AAV) was employed to specifically knockdown of GLUT1 in hippocampal microglia to assess its impact on stressed-mice. Results Herein, we found that chronic stress induced remarkable hippocampal microglial proinflammatory activation and neuroinflammation, which were involved in the development of stress-related spatial learning and memory impairment. Mechanistically, elevated hippocampal glucose level post-stress was revealed to be a key regulator of proinflammatory microglial activation via specifically increasing the expression of microglial GLUT1. GLUT1 overexpression promoted microglial proinflammatory phenotype while inhibiting GLUT1 function mitigated this effect under high glucose. Furthermore, specific downregulation of hippocampal microglial GLUT1 in stressed-mice relieved microglial proinflammatory activation, neuroinflammation, and spatial learning and memory injury. Finally, the NF-κB signaling pathway was demonstrated to be involved in the regulatory effect of GLUT1 on microglia. Conclusions We demonstrate that elevated glucose and GLUT1 expression induce microglia proinflammatory activation, contributing to stress-associated spatial memory dysfunction. These findings highlight significant interplay between metabolism and inflammation, presenting a possible therapeutic target for stress-related cognitive disorders.

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“…The mentioned study described similar findings in the intestine. Sun et al [ 83 ] found that in mice in a chronic mild stress model, depression-like states were accompanied by hippocampal BBB breakdown and claudin-5 downregulation. Antidepressant treatment reversed these changes.…”

Section: Discussionmentioning

confidence: 99%

Treatment with Glycyrrhiza glabra Extract Induces Anxiolytic Effects Associated with Reduced Salt Preference and Changes in Barrier Protein Gene Expression

Murck,

Karailiev,

Karailievova

et al. 2024

Nutrients

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We have previously identified that low responsiveness to antidepressive therapy is associated with higher aldosterone/cortisol ratio, lower systolic blood pressure, and higher salt preference. Glycyrrhiza glabra (GG) contains glycyrrhizin, an inhibitor of 11β-hydroxysteroid-dehydrogenase type-2 and antagonist of toll-like receptor 4. The primary hypothesis of this study is that food enrichment with GG extract results in decreased anxiety behavior and reduced salt preference under stress and non-stress conditions. The secondary hypothesis is that the mentioned changes are associated with altered gene expression of barrier proteins in the prefrontal cortex. Male Sprague-Dawley rats were exposed to chronic mild stress for five weeks. Both stressed and unstressed rats were fed a diet with or without an extract of GG roots for the last two weeks. GG induced anxiolytic effects in animals independent of stress exposure, as measured in elevated plus maze test. Salt preference and intake were significantly reduced by GG under control, but not stress conditions. The gene expression of the barrier protein claudin-11 in the prefrontal cortex was increased in control rats exposed to GG, whereas stress-induced rise was prevented. Exposure to GG-enriched diet resulted in reduced ZO-1 expression irrespective of stress conditions. In conclusion, the observed effects of GG are in line with a reduction in the activity of central mineralocorticoid receptors. The treatment with GG extract or its active components may, therefore, be a useful adjunct therapy for patients with subtypes of depression and anxiety disorders with heightened renin–angiotensin–aldosterone system and/or inflammatory activity.

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Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors

Cited by 22 publications

References 41 publications

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice

Treatment with Glycyrrhiza glabra Extract Induces Anxiolytic Effects Associated with Reduced Salt Preference and Changes in Barrier Protein Gene Expression

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