Ds-HMGB1 and fr-HMGB induce depressive behavior through neuroinflammation in contrast to nonoxid-HMGB1

Lian, Yong‐Jie; Gong, Hongyun; Wu, Teng-Yun; Su, Wen‐Jun; Zhang, Yi; Yang, Yuanyuan; Wei, Peng; Zhang, Ting; Zhou, Jingxu; Jiang, Chun‐Lei; Wang, Yunxia

doi:10.1016/j.bbi.2016.09.017

Cited by 86 publications

(79 citation statements)

References 76 publications

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“…Other studies support this hypothesis and our findings are in agreement with these investigations [6, 16, 32, 38]. Lian et al [32] observed similar cytokine production and depressive-like behaviour after intracerebroventricular injection of either ds- or fr-HMGB1, and these effects were mediated via TLR4 and not RAGE or CXCL12, the receptors for fr-HMGB1. Furthermore, Balosso et al [16] reported that ds- and fr-HMGB1 enhanced NMAD-induced Ca 2+ influx equally well, and the frequency and duration of kainic acid induced seizures in mice.…”

Section: Discussionsupporting

confidence: 93%

“…Indeed, fr-HMGB1 has a relatively short half-life (∼17 min) in biological fluids such as serum and saliva [37]. Other studies support this hypothesis and our findings are in agreement with these investigations [6, 16, 32, 38]. Lian et al [32] observed similar cytokine production and depressive-like behaviour after intracerebroventricular injection of either ds- or fr-HMGB1, and these effects were mediated via TLR4 and not RAGE or CXCL12, the receptors for fr-HMGB1.…”

Section: Discussionsupporting

confidence: 92%

“…Upregulation of IL-1β mRNA expression by HMGB1 during ethanol-induced neuro-immune signalling is TLR4 dependent and is reduced in the presence of specific receptor antagonists or using TLR4-specific siRNA [11]. Cerebroventricular ds-HMGB1 and to a lesser extent fr-HMGB1 also increase TNF-α production [32]. Recently, Frank et al [33] found that ds-HMGB1 injected into the cisterna magna increases NF-κBIα mRNA, NLRP3 mRNA, and IL-1β protein expression in the hippocampus within 2 h. In contrast to our study, no cytokine production was detected after fr-HMGB1 exposure; this may be due to differences in the redox state in different brain regions which affect the modification of the protein in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Agalave et al [15] found that ds-HMGB1, but not the fully reduced or oxidised isoforms, mediates TLR4-dependent mechanical hypersensitivity. In addition, intracerebroventricular ds- and fr-HMGB1 induce depressive behaviour [32], and elevated HMGB1 levels are associated with the development of systemic sickness syndrome and cognitive dysfunction [12]. …”

Section: Discussionmentioning

confidence: 99%

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Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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Background: Neuroinflammation triggered by infection or trauma is the cause of central nervous system dysfunction. High-mobility group box 1 protein (HMGB1), released from stressed and dying brain cells, is a potent neuroinflammatory mediator. The proinflammatory functions of HMGB1 are tightly regulated by post-translational redox modifications, and we here investigated detailed neuroinflammatory responses induced by the individual redox isoforms. Methods: Male Dark Agouti rats received a stereotactic injection of saline, lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1, and were accessed for blood-brain barrier modifications using magnetic resonance imaging (MRI) and inflammatory responses by immunohistochemistry. Results and Conclusions: Significant blood-brain barrier disruption appeared 24 h after injection of lipopolysaccharide, disulfide HMGB1, or fully reduced HMGB1 compared to controls, as assessed in post-gadolinium T1-weighted MRI images and confirmed by increased uptake of FITC-conjugated dextran. Immunohistochemistry revealed that both HMGB1 isoforms also induced a local production of IL-1β. Additionally, disulfide HMGB1 increased major histocompatibility complex class II expression and apoptosis. Together, the results demonstrate that extracellular, cerebral HMGB1 causes significant blood-brain barrier disruption in a redox-independent manner and activates several components of neuroinflammation. Blocking HMGB1 might potentially improve clinical outcome in conditions such as stroke and traumatic brain injury.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

et al. 2018

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“…The specific mechanisms linking aroused innate immunity with MDD are still unclear. Several different signals have been proposed to be involved in transforming stress into activation of innate immunity, including chronic glucocorticoids exposure [9, 10], gut microbiome-brain interactions [11], and alarm signals [12, 13]. …”

Section: Introductionmentioning

confidence: 99%

Antidepressants Improve Negative Regulation of Toll-Like Receptor Signaling in Monocytes from Patients with Major Depression

Hung¹

2018

Neuroimmunomodulation

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Objective: Changes in the brain’s inflammatory status can lead to psychopathological responses, especially depression. Using animal models, recent studies have revealed that this pathology is due, in part, to innate immune responses of monocytes. Methods: We focus on the involvement of Toll-like receptors (TLRs) and expression of genes encoding their negative regulators, SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2, and TNFAIP3, in CD14⁺ monocytes from 34 patients with major depressive disorder (MDD) and 33 healthy controls before and after treatment with antidepressants. We also seek to investigate their association with depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17). Results: mRNA expression of all TLRs, except TLR3 and -5, was significantly higher in monocytes from patients with MDD than in those from controls. Conversely, the “brakes” in TLR signaling, including TOLLIP, MyD88s, NOD2, and TNFAIP3, were downregulated. In clinical findings, the remission group showed higher baseline TLR4 and lower baseline IRAK3 mRNA levels but only baseline elevated SOCS1 mRNA levels, which were inversely correlated with HAMD-17 scores, predicting worsened outcome in MDD patients. In addition, TNFAIP3 mRNA levels were increased by antidepressant treatment. Conclusion: Collectively, our findings suggest a role for dysregulation of TLR signaling in monocytes in MDD and identify a balancing effect of antidepressants on this dysregulation.

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Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

Jiang

Zeng

et al. 2022

Brain and Behavior

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Background: High mobility group box 1 (HMGB1) released by neurons and microglia was demonstrated to be an important mediator in depressive-like behaviors induced by chronic unpredictable mild stress (CUMS), which could lead to the imbalance of two different metabolic approaches in kynurenine pathway (KP), thus enhancing glutamate transmission and exacerbating depressive-like behaviors. Evidence showed that HMGB1 signaling might be regulated by Connexin (Cx) 36 in inflammatory diseases of central nervous system (CNS). Our study aimed to further explore the role of Cx36 in depressive-like behaviors and its relationship with HMGB1.Methods: After 4-week chronic stress, behavioral tests were conducted to evaluate depressive-like behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Western blot analysis and immunofluorescence staining were used to observe the expression and location of Cx36. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the concentrations of inflammatory cytokines. And the excitability and inward currents of hippocampal neurons were recorded by whole-cell patch clamping. Results:The expression of Cx36 was significantly increased in hippocampal neurons of mice exposed to CUMS, while treatment with glycyrrhizinic acid (GZA) or quinine could both down-regulate Cx36 and alleviate depressive-like behaviors. The proinflammatory cytokines like HMGB1, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were all elevated by CUMS, and application of GZA and quinine could decrease them. In addition, the enhanced excitability and inward currents of hippocampal neurons induced by lipopolysaccharide (LPS) could be reduced by either GZA or quinine.Conclusions: Inhibition of Cx36 in hippocampal neurons might attenuates HMGB1mediated depressive-like behaviors induced by CUMS through down-regulation of the proinflammatory cytokines and reduction of the excitability and intracellular ion overload.

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Ds-HMGB1 and fr-HMGB induce depressive behavior through neuroinflammation in contrast to nonoxid-HMGB1

Cited by 86 publications

References 76 publications

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

Neuroinflammation in Response to Intracerebral Injections of Different HMGB1 Redox Isoforms

Antidepressants Improve Negative Regulation of Toll-Like Receptor Signaling in Monocytes from Patients with Major Depression

Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

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