scholarly journals Activation of the hippocampal LXRβ improves sleep-deprived cognitive impairment by inhibiting neuroinflammation

2021 ◽  
Author(s):  
Chen Qiu ◽  
Min Wang ◽  
Wen Yu ◽  
Zheng Rong ◽  
He-Sheng Zheng ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
High Mobility ◽  
Liver X Receptors ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Potential Therapeutic Target ◽  
Cognitive Improvement ◽  
X Receptors ◽  
Dual Agonist ◽  
Anti Inflammation

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.

scholarly journals TNF-α Activates High-Mobility Group Box 1 - Toll-Like Receptor 4 Signaling Pathway in Human Aortic Endothelial Cells

2016 ◽  
Vol 38 (6) ◽  
pp. 2139-2151 ◽  
Author(s):  
Won Seok Yang ◽  
Nam Jeong Han ◽  
Jin Ju Kim ◽  
Mee Jeong Lee ◽  
Su-Kil Park
Keyword(s):  
Signal Transduction ◽  
Endothelial Cells ◽  
High Mobility ◽  
Neutralizing Antibody ◽  
High Mobility Group ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Aortic Endothelial Cells ◽  
Tnf Α ◽  
Human Aortic Endothelial Cells

Background/Aims: Toll-like receptor 4 (TLR4) interacts with endogenous substances as well as lipopolysaccharide. We explored whether TLR4 is implicated in tumor necrosis factor-α (TNF-α) signal transduction in human aortic endothelial cells. Methods: The pathway was evaluated by transfection of siRNAs, immunoprecipitation and Western blot analysis. Results: TNF-α activated spleen tyrosine kinase (Syk) within 10 min, which led to endothelin-1 (ET-1) production. TLR4 was also rapidly activated by TNF-α stimulation, as shown by recruitment of interleukin-1 receptor-associated kinase 1 to TLR4 and its adaptor molecule, myeloid differentiation factor 88 (MyD88). siRNA depletion of TLR4 markedly attenuated TNF-α-induced Syk activation and ET-1 production. TLR4 inhibitor (CLI-095), TLR4-neutralizing antibody and siRNA depletion of MyD88 also attenuated TNF-α-induced Syk activation. Syk was co-immunoprecipitated with TLR4, and TNF-α activated Syk bound to TLR4. High-mobility group box 1 (HMGB1) was rapidly released and associated with TLR4 after TNF-α stimulation with a peak at 5 min, which was prevented by N-acetylcysteine, an antioxidant. Glycyrrhizin (HMGB1 inhibitor), HMGB1-neutralizing antibody and siRNA depletion of HMGB1 all suppressed TNF-α-induced Syk activation and ET-1 production. Conclusion: Upon TNF-α stimulation, TLR4 is activated by HMGB1 that is immediately released after the generation of reactive oxygen species, and plays a crucial role in the signal transduction.

scholarly journals High Mobility Group Box 1 Contributes to the Pathogenesis of Experimental Pulmonary Hypertension via Activation of Toll-like Receptor 4

2012 ◽  
Vol 18 (12) ◽  
pp. 1509-1518 ◽  
Author(s):  
Eileen M Bauer ◽  
Richard Shapiro ◽  
Han Zheng ◽  
Ferhaan Ahmad ◽  
David Ishizawar ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Mobility ◽  
High Mobility Group ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals Antiaging Factor Klotho Retards the Progress of Intervertebral Disc Degeneration through the Toll-Like Receptor 4-NF-κB Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Fangfang Bi ◽  
Wenbo Liu ◽  
Zongtao Wu ◽  
Chen Ji ◽  
Cuicui Chang
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Acute Inflammation ◽  
Protective Effects ◽  
Toll Like Receptor ◽  
Inhibitory Effects ◽  
Toll Like Receptor 4 ◽  
Disc Injury ◽  
Anti Inflammation

Antiaging protein Klotho exhibits impressive properties of anti-inflammation, however is declined early after intervertebral disc injury, making Klotho restoration an attractive strategy of treating intervertebral disc inflammatory disorders. Here, we have found that Klotho is enriched in nucleus pulposus (NP) cells and Klotho overexpression attenuates H2O2-induced acute inflammation essentially via suppressing Toll-like receptor 4 (TLR4). The proinflammatory NF-κB signaling and cytokine expressions paralleled with Klotho repression and TLR4 elevation in both NP cells (H2O2 treatment) and rat intervertebral disc (needle puncture treatment). Overexpression of TLR4 downregulated expression of Klotho, whereas interfering TLR4 expression diminished the inhibitory effects of H2O2 on Klotho in NP cells. Consistently, Klotho knockdown by RNA interferences largely diminished the anti-inflammatory and intervertebral disc protective effects in an Intervertebral Disc Degeneration (IDD) model. Thus, our study indicates that TLR4-NF-κB signaling and Klotho form a negative-feedback loop in NP cells. Also, we demonstrate that the expression of Klotho is regulated by the balance between upregulation and downregulation of TLR4-NF-κB signaling.

scholarly journals Extracellular High Mobility Group Box-1 (HMGB1) Inhibits Enterocyte Migration via Activation of Toll-like Receptor-4 and Increased Cell-Matrix Adhesiveness

2009 ◽  
Vol 285 (7) ◽  
pp. 4995-5002 ◽  
Author(s):  
Shipan Dai ◽  
Chhinder Sodhi ◽  
Selma Cetin ◽  
Ward Richardson ◽  
Maria Branca ◽  
...  
Keyword(s):  
High Mobility ◽  
High Mobility Group ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Cell Matrix
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