Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior
Open accessAbstract
Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1-3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice.
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Exposure to an initial series of acute footshocks increased NLRP3 as well as mature caspase-1 in the hippocampus.
“They found that exposure to an initial series of acute footshocks increased NLRP3 as well as mature caspase-1 in the hippocampus.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
If a second series of footshocks was administered 24 h after the initial series, IL-1β protein was increased, suggesting that the initial series of shocks had primed the NLRP3 inflammasome.
“if a second series of footshocks was administered 24 h after the initial series of footshocks, IL-1β protein was increased, suggesting that the initial series of shocks had primed the NLRP3 inflammasome.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
Intranasal pre-treatment with HMGB1 siRNA blocked stress-induced increases in IL-1β protein.
“Intranasal pre-treatment with HMGB1 siRNA was found to significantly reduce hippocampal protein levels of HMGB1 and blocked stress-induced increases in IL-1β protein, suggesting that HMGB1 mediates the priming effects of stress on IL-1β.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
Exposure to a second series of footshocks 24 h after the initial series resulted in increased hippocampal IL-1β protein and mRNA.
“As noted earlier, initial stress exposure failed to increase IL-1β protein; however, exposure to second series of footshocks 24 h after the initial series of footshocks resulted in increased hippocampal IL-1β protein and mRNA.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
In Cheng et al. (2016), exposure to a series of footshocks increased hippocampal active NF-κB, NLRP3, and mature caspase-1 protein.
“Consistent with these findings, Cheng et al (2016) also found that exposure to a series of footshocks increased hippocampal protein levels of HMGB1 along with increased active NF-κB, NLRP3, and mature caspase-1 protein (Cheng et al, 2016).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
In TLR4 KO mice, the effects of stress on NF-κB, NLRP3, and mature caspase-1 were blocked.
“Further, Cheng et al (2016) found that the effects of stress on NF-κB, NLRP3, and mature caspase-1 were also blocked in TLR4 KO mice.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
In TLR4 KO mice, stress effects on HMGB1 were not blocked.
“However, stress effects on HMGB1 were not blocked in TLR4 KO mice.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
Intranasal pre-treatment with HMGB1 siRNA significantly reduced hippocampal protein levels of HMGB1.
“Intranasal pre-treatment with HMGB1 siRNA was found to significantly reduce hippocampal protein levels of HMGB1 and blocked stress-induced increases in IL-1β protein, suggesting that HMGB1 mediates the priming effects of stress on IL-1β.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
In Cheng et al. (2016), exposure to a series of footshocks increased hippocampal protein levels of HMGB1.
“Consistent with these findings, Cheng et al (2016) also found that exposure to a series of footshocks increased hippocampal protein levels of HMGB1 along with increased active NF-κB, NLRP3, and mature caspase-1 protein (Cheng et al, 2016).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
Exposure to the second series of footshocks resulted in a potentiated HMGB1 response in the hippocampus.
“It should be noted that exposure to the second series of footshocks resulted in a potentiated HMGB1 response in the hippocampus, suggesting that HMGB1 may serve as both the NLRP3 inflammasome priming stimulus as well as the activating stimulus.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
Upon exposure to a subsequent series of footshocks, the IL-1β response was potentiated.
“Upon exposure to a subsequent series of footshocks, the IL-1β response was potentiated.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Cheng et al, 2016
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- Authors
- Cheng, Y., Pardo, M., Armini, R. D. S., Martinez, A., Mouhsine, H., Zagury, J.-F., Jope, R. S., & Beurel, E.
- Affiliations
- University of Miami (US)
- Conservatoire National des Arts et Métiers (FR)
- Corresponding author
- Jope, Richard S.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 53
- Pages
- 207-222
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC4783243
- OpenAlex
- W2226515760
- Cited by
- 174
- References
- 102
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 16 · 2023: 22 · 2022: 16 · 2021: 22 · 2020: 23 · 2019: 13 · 2018: 11 · 2017: 14 · 2016: 9
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIMH (MH095380, MH038752, MH090236, MH104656)
- Expedition Inspiration Foundation
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- depression-like behavior, TLR4 signaling, glycogen synthase kinase-3, hippocampus, cytokines, chemokines, HMGB1, NF-κB, NLRP3 inflammasome, learned helplessness, inescapable footshock, fluoxetine, TDZD-8, TNF-α, damage-associated molecular patterns, antidepressant resistance
- MeSH terms
- Animals, Depression, Fluoxetine, Hippocampus, Inflammation, Male, Stress, Physiological, Tumor Necrosis Factor-alpha, Neuroimmunomodulation, Signal Transduction, Up-Regulation, Cytokines, NF-kappa B, Mice, Knockout, HMGB1 Protein, Glycogen Synthase Kinase 3, Toll-Like Receptor 4, Mice, Inflammasomes
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