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Stress Induces the Danger-Associated Molecular Pattern HMGB-1 in the Hippocampus of Male Sprague Dawley Rats: A Priming Stimulus of Microglia and the NLRP3 Inflammasome
Open accessAbstract
Exposure to acute and chronic stressors sensitizes the proinflammatory response of microglia to a subsequent immune challenge. However, the proximal signal by which stressors prime microglia remains unclear. Here, high mobility group box-1 (HMGB-1) protein was explored as a potential mediator of stress-induced microglial priming and whether HMGB-1 does so via the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome. Exposure to 100 inescapable tail shocks (ISs) increased HMGB-1 and NLRP3 protein in the hippocampus and led isolated microglia to release HMGB-1 ex vivo. To determine whether HMGB-1 signaling is necessary for stress-induced sensitization of microglia, the HMGB-1 antagonist BoxA was injected into the cisterna magna before IS. Hippocampal microglia were isolated 24 h later and stimulated with LPS ex vivo to probe for stress-induced sensitization of proinflammatory responses. Previous IS potentiated gene expression of NLRP3 and proinflammatory cytokines to LPS, that is, microglia were sensitized. Treatment with BoxA abolished this effect. To determine whether HMGB-1 is sufficient to prime microglia, IS was replaced with intracerebral administration of disulfide or fully reduced HMGB-1. Intracerebral disulfide HMGB-1 mimicked the effect of the stressor, because microglia isolated from HMGB-1-treated rats expressed exaggerated NLRP3 and proinflammatory cytokine expression after LPS treatment, whereas fully reduced HMGB-1 had no effect. The present results suggest that the CNS innate immune system can respond to an acute stressor as if it were cellular damage, thereby releasing the danger signal HMGB-1 in the brain to prime microglia by acting on the NLRP3 inflammasome, in preparation for a later immune challenge.
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“We have also found that exposure to acute stress, in this case inescapable tailshock, increases NLRP3 protein in the hippocampus up to 24 h after stress treatment; however, microglial IL-1β was not increased at that time-point post stress (Weber et al, 2015).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Weber et al, 2015
In the citing paper
“we found that intracisterna magna administration of an HMGB1 antagonist (box A) before stress exposure blocked the potentiated microglial proinflammatory response to an immune challenge ex vivo.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Weber et al, 2015
In the citing paper
“We recently found that exposure to an acute stressor (inescapable tailshock) induces HMGB1 in the hippocampus concomitant with increased protein levels of active NF-κB and NLRP3 protein (Weber et al, 2015).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Weber et al, 2015
In the citing paper
“treatment of hippocampal microglia with the TLR4 agonist LPS resulted in a potentiated IL-1β response in animals exposed to stress 24 h earlier, suggesting that the NLRP3 inflammasome was primed by initial stress exposure.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Weber et al, 2015
In the citing paper
“Recently, HMGB-1 was found to be highly expressed in the CNS and was implicated in a variety of neuroinflammatory conditions (Kang et al, 2014), including stress (Weber et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Weber et al, 2015
In the citing paper
“For example, HMGB-1 protein is increased in the hippocampus following a series of repeated tail shock and persists for at least 24 h later (Weber et al, 2015).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Weber et al, 2015
In the citing paper
“Pharmacological antagonism of the receptor targets for HMGB-1 blocked the effect of stress to prime microglia (Weber et al, 2013(Weber et al, , 2015)).”
From Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal (2017) · cites this paper as Weber et al, 2015
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“The NLRP3 inflammasome contributes to multiple processes, such as cell immune damage, apoptosis, and inflammation [11, 13].”
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“While AMPH exposure alone may not result in expression changes in the inflammasome, several studies have found that prior exposure to glucocorticoids or stress activates this signaling cascade (Frank et al., 2014; Frank et al., 2015; Weber et al., 2015; Zhang et al., 2015; Sobesky et al., 2016).”
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“The timing of HMGB1 administration was determined based on findings that brain ischemia and severe stress induce HMGB1 secretion in serum and CSFwith a maximum level reached 24 h after severe brain insults (Kim et al. 2006; Weber et al. 2015).”
BackgroundEnduring and Sex-specific Changes in Hippocampal Gene Expression after a Subchronic Immune Challenge
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“Prior studies have implicated NLRP3 in stress-induced priming of neuroinflammatory processes (Alcocer-Gomez et al., 2016; Feng et al., 2019; Iwata et al., 2016; Pan et al., 2014; Weber et al., 2015).”
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Possible antidepressant mechanism of acupuncture: targeting neuroplasticity
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Microglia-Induced Maladaptive Plasticity Can Be Modulated by NeuropeptidesIn Vivo
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“Indeed, stress might induce a priming stimulus for microglia via increased high mobility group box-1 protein and, in turn, produce microglial overreactivity to LPS challenge via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing protein 3 inflammasome [35].”
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Yılmaz, N., Yelboğa, Z., Yılmaz, Y., & Demirpençe, Ö. (2020) · Journal of Medical Biochemistry · doi:10.5937/jomb0-28108 · Cited by 11
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Metadata
- Authors
- Weber, M. D., Frank, M. G., Tracey, K. J., Watkins, L. R., & Maier, S. F.
- Affiliations
- University of Colorado Boulder (US)
- Northwell Health (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-01-07
- Volume
- 35
- Issue
- 1
- Pages
- 316-324
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4287150
- OpenAlex
- W2087987871
- Cited by
- 215
- References
- 46
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 12 · 2023: 11 · 2022: 20 · 2021: 21 · 2020: 25 · 2019: 19 · 2018: 24 · 2017: 25 · 2016: 21 · 2015: 16
- FWCI
- 15.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH096224, R21MH096224)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- HMGB1, NLRP3 inflammasome, microglial priming, hippocampus, inflammatory cytokines, lipopolysaccharide response, damage-associated molecular patterns
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, Hippocampus, Male, Stress, Psychological, Rats, Sprague-Dawley, Microglia, Receptors, Cytoplasmic and Nuclear, HMGB1 Protein, Rats, Inflammasomes
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