Toll-Like Receptor 4/MyD88–Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage

Abstract Sleep deprivation (SD) leads to cognitive impairment due to neuroinflammation associated with impaired hippocampal neuronal plasticity and memory processes. Liver X receptors (LXRs), including LXRα and LXRβ isoforms, are crucial for synaptic plasticity as well as anti-inflammation. However, the potential roles of LXRs in the pathogenesis of cognitive impairment induced by SD remain unclear. We revealed that SD resulted in LXRβ reduction in hippocampus, which was associated with upregulated expression of high mobility group box1 (HMGB1)/toll-like receptor 4 (TLR4)/NF-κB p65, and knockdown of hippocampal LXRβ by shRNA (shLXRβ) led to cognitive impairment. GW3965, a dual agonist for both LXRα and LXRβ, ameliorated SD-induced cognitive impairment by inhibiting microglia activation, suppressing HMGB1/TLR4/NF-κB p65 pathway, and ultimately affecting the hippocampal expression of inflammatory cytokines in SD mice. LXRβ knockdown by shLXRβ, abrogated GW3965-mediated the inhibition of HMGB1/TLR4/NF-κB p65 pathway, therefore abolished the cognitive improvement. Moreover, inhibition of HMGB1 by glycyrrhizin (GLY) synergistic promoted GW3965-mediated anti-inflammation in activated microglia after LPS/ATP stimulation and facilitated the cognitive improvement after GW administration by activating LXRβ. All the data suggested that GW3965 ameliorated impaired cognition in SD mice by suppressing HMGB1/TLR4/NF-κB p65 pathway followed LXRβ activation. This study correlates a deficit of LXRβ in cognitive dysfunction in SD associated with HMGB1 inflammatory pathway in hippocampus, and LXRs may serve as a potential therapeutic target for cognitive impairment with anti-inflammation.

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Deep Succinylproteomics of Brain Tissues from Intracerebral Hemorrhage with Inhibition of Toll-Like Receptor 4 Signaling

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01144-w ◽

2021 ◽

Author(s):

Yan-Jing Liang ◽

Yuan-Rui Yang ◽

Chuan-Yuan Tao ◽

Su-Hao Yang ◽

Xin-Xiao Zhang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Brain Tissues

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The role of Toll-like receptor 4 in apoptosis of brain tissue after induction of intracerebral hemorrhage

Journal of Neuroinflammation ◽

10.1186/s12974-019-1634-x ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 4

Author(s):

Xiaowei Fei ◽

Yeting He ◽

Jia Chen ◽

Weitao Man ◽

Chen Chen ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Knockout Mice ◽

Neuronal Apoptosis ◽

Inflammatory Factors ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Tnf Α ◽

Apoptotic Effect

Abstract Background Inflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis. Methods We performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant. Results TLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice. Conclusions We conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.

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Toll-Like Receptor 4 Reduces Oxidative Injury via Glutathione Activity in Sheep

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/9151290 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 6

Author(s):

Shoulong Deng ◽

Kun Yu ◽

Qian Wu ◽

Yan Li ◽

Xiaosheng Zhang ◽

...

Keyword(s):

Oxidative Injury ◽

Innate Immune ◽

Gram Negative Bacteria ◽

Superoxide Dismutase 1 ◽

Toll Like Receptor ◽

Tlr4 Expression ◽

Toll Like Receptor 4 ◽

Transgenic Sheep ◽

Glutamylcysteine Synthetase ◽

Inflammatory Infiltrates

Toll-like receptor 4 (TLR4) is an important sensor of Gram-negative bacteria and can trigger activation of the innate immune system. Increased activation of TLR4 can lead to the induction of oxidative stress. Herein, the pathway whereby TLR4 affects antioxidant activity was studied. In TLR4-overexpressing sheep, TLR4 expression was found to be related to the integration copy number when monocytes were challenged with lipopolysaccharide (LPS). Consequently, production of malondialdehyde (MDA) was increased, which could increase the activation of prooxidative stress enzymes. Meanwhile, activation of an antioxidative enzyme, glutathione peroxidase (GSH-Px), was increased. Real-time PCR showed that expression of activating protein-1 (AP-1) and the antioxidative-related genes was increased. By contrast, the expression levels of superoxide dismutase 1 (SOD1) and catalase (CAT) were reduced. In transgenic sheep, glutathione (GSH) levels were dramatically reduced. Furthermore, transgenic sheep were intradermally injected with LPS in each ear. The amounts of inflammatory infiltrates were correlated with the number of TLR4 copies that were integrated in the genome. Additionally, the translation ofγ-glutamylcysteine synthetase (γ-GCS) was increased. Our findings indicated that overexpression of TLR4 in sheep could ameliorate oxidative injury through GSH secretion that was induced by LPS stimulation. Furthermore, TLR4 promotedγ-GCS translation through the AP-1 pathway, which was essential for GSH synthesis.

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Hepatocyte toll-like receptor 4 mediates lipopolysaccharide-induced hepcidin expression

Experimental & Molecular Medicine ◽

10.1038/emm.2017.207 ◽

2017 ◽

Vol 49 (12) ◽

pp. e408-e408 ◽

Cited By ~ 23

Author(s):

Yong-Soo Lee ◽

Yong-Hoon Kim ◽

Yoon Seok Jung ◽

Ki-Sun Kim ◽

Don-Kyu Kim ◽

...

Keyword(s):

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Hepcidin Expression

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Deep Succinylproteomics of Brain Tissues of Intracerebral Hemorrhage with Inhibition of Toll-like Receptor 4 Signaling

10.21203/rs.3.rs-392813/v1 ◽

2021 ◽

Author(s):

Yan-Jing Liang ◽

Yuan-Rui Yang ◽

Chuan-Yuan Tao ◽

Su-Hao Yang ◽

Xin-Xiao Zhang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Acid Metabolism ◽

High Resolution Mass Spectrometry ◽

Membrane Vesicle ◽

Transcriptome Data ◽

Toll Like Receptor ◽

Brain Protein ◽

Toll Like Receptor 4 ◽

Proteomics Approach ◽

Induced Changes

Abstract The details of Toll-like receptor (TLR) 4 signaling affects protein succinylation in intracerebral hemorrhage (ICH) brains remains completely unclear. In this study, we constructed mice ICH models to investigate the changes in ICH-associated brain protein succinylation with the treatment of TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized a concentration of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase in 29 succinyllysine sites of 28 succinylated proteins and reduction of 24 succinyllysine sites on 23 succinylated proteins in ICH brains. Both the TAK242 treatment induced hypersuccinylated and hyposuccinylated proteins in ICH brains were mainly located in mitochondria and cytoplasm. GO analysis showed that TAK242 treatment induced changes in ICH-associated succinylated proteins were mostly located in synapse, membrane, vesicle, etc., and enriched in many processes, such as metabolism, synapse, myeline, etc.. KEGG analysis showed that TAK242 induced downregulation of succinylation was significantly linked to fatty acid metabolism and lysosome. Moreover, a combination analysis of our succinylproteomic data with previously published transcriptome data identified that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed into neurons, astrocytes and endothelial cells; and 7 and 3 of these succinylated proteins significantly high express in neurons and astrocytes, respectively. In conclusion, our analyses uncover a number of TLR4 signaling affected succinylation processes and pathways in mouse ICH brains and provide new insights for understanding ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622.

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