CoChat
Sign Up
Cited by 216Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsStress Responses and Cortisol

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

Open access
Fleshner, Monika, Frank, Matthew, Maier, Steven F·2017·Neuropsychopharmacology
DOI 10.1038/npp.2016.125PMC PMC5143484
Open this paper in CoChat — free accountOpen PDF

Abstract

Major depressive disorder (MDD) and other mood disorders remain difficult to effectively treat, and innovative interventions and therapeutic targets are needed. Psychological stressors and inappropriate inflammation increase the risk and severity of mood disorders; however, only recently have the importance of sterile inflammatory processes in this effect been revealed. This review will introduce the reader to pathogen vs sterile inflammation, inflammatory receptor-ligand interactions, microbial-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and the more recent discovery of the role of the inflammasome in peripheral and central nervous system cytokine/chemokine inflammatory responses. The review will focus on current preclinical and clinical evidence that sterile inflammation and inflammasome-dependent signaling may contribute to mood disorders. By understanding these inflammatory signaling processes, new approaches for quieting chronic or inappropriate inflammatory states may be revealed and this could serve as novel pharmacological targets for the treatment of mood disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that psychological stress can trigger sterile inflammation through danger-associated molecular patterns (DAMPs) and NLRP3 inflammasome activation, contributing to mood disorders. Preclinical and clinical evidence links stress-evoked DAMP signaling, microglial priming, and IL-1β to depressive-like behaviors, suggesting inflammasome-targeted therapeutics.

Key findings

  • Stressor exposure can produce sterile inflammation: rats exposed to uncontrollable tailshock, a predatory cat, or ferret odor had increased blood DAMPs (e.g., Hsp72, uric acid crystals) with little evidence of cell death (low LDH); tailshock-evoked Hsp72 release depended on α-adrenergic, not β or glucocorticoid, receptor signaling.
  • NLRP3 inflammasome signaling is implicated in mood disorders: patients with depression had increased NLRP3 and caspase-1 expression in peripheral blood mononuclear cells; in rats, 12 weeks of chronic unpredictable stress (CUS) increased IL-1β mRNA and mature IL-1β protein, NLRP3 protein/mRNA, and mature caspase-1 in the prefrontal cortex, effects blunted by chronic fluoxetine during weeks 6–12.
  • Causal animal evidence: 30 days of 2-h daily immobilization induced depressive-like behavior and increased mature IL-1β in PFC and hippocampus in wild-type mice, but the depressive phenotype and IL-1β increases were abrogated in NLRP3 knockout mice; 21 days of CUS effects on sucrose preference were abrogated in NLRP3 knockout mice and ameliorated by peripheral IL-1β-blocking antibody.
  • DAMP mechanisms: acute immobilization (60 min) caused intrahippocampal ATP release and NLRP3 activation/IL-1β; a P2X7 receptor antagonist blocked acute effects, and chronic P2X7 antagonist ameliorated CUS-induced depressive-like behaviors. Initial footshock increased hippocampal NLRP3 and mature caspase-1 without IL-1β, but a second footshock 24 h later increased IL-1β; HMGB1 siRNA and TLR4 knockout blocked components of this response.

Methods

  • Narrative review; no systematic review protocol, database search strategy, or inclusion/exclusion criteria are stated.
  • Synthesizes clinical studies in MDD/PTSD and preclinical rodent stress models (e.g., uncontrollable tailshock, chronic unpredictable stress, chronic immobilization, footshock, predator odor); includes one previously unpublished study in Figure 2 using adult male Sprague-Dawley rats (8 per group), ferret urine odor 10 min/day for 7 days, and serum Hsp72 measured by ELISA.
  • Main analysis is a conceptual synthesis of pathogen vs sterile inflammation, DAMP/PAMP/MAMP signaling, NLRP3 two-step priming/activation, microglial neuroinflammation, and candidate therapeutics; no meta-analysis.

Limitations

  • Stated: correlative findings (e.g., Pan et al 2014) preclude definitive causal conclusions about the NLRP3 inflammasome in CUS-induced depressive-like behaviors and neuroinflammatory processes.
  • Stated: it is not possible to conclude that ATP/P2X7 signaling is restricted to the brain because both the P2X7 receptor antagonist and Nlrp3 knockout could affect peripheral as well as brain sterile inflammation; it is also unknown whether stress mediators such as noradrenaline and glucocorticoids induce DAMPs.
  • Evident: as a narrative review, it lacks systematic search and quality assessment; many conclusions rely on animal models with specific stressors, and clinical evidence is largely associative.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/npp.2016.125

Cites

101 of 101 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 119 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The release of Hsp72 after tailshock is dependent on α-adrenergic, but not β- or glucocorticoid, receptor signaling.

    “the release of Hsp72 (a possible DAMP) after tailshock is dependent on α-adrenergic, but not βor glucocorticoid, receptor signaling (Johnson et al, 2005;Johnson and Fleshner, 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Johnson et al, 2005 source

      Not checked in the free run.

    • cites Johnson and Fleshner, 2006 source

      Not checked in the free run.

  • Premisecitation

    The stress-evoked cytokine/chemokine response is an example of sterile inflammation.

    “The stress-evoked cytokine/chemokine response is an example of sterile inflammation (Fleshner, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fleshner, 2013 source

      Not checked in the free run.

  • Premisecitation

    Children with higher plasma IL-6 following a motor vehicle accident had a greater chance of developing PTSD compared with children without elevated IL-6 or controls.

    “Pervanidou et al (2007), for example, reported that children with higher concentrations of plasma IL-6 following a motor vehicle accident had a greater chance of developing PTSD compared with children who did not have elevated IL-6 after the accident or controls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pervanidou et al, 2007 source

      Not checked in the free run.

  • Interpretationcitation

    Stressor exposure may stimulate DAMP release that is not dependent on necrotic cell death.

    “It appears therefore that stressor exposure may stimulate DAMP release that is not dependent on necrotic cell death.”
    Quote in the paperSubstantial claim
  • Premisecitation

    CRP concentration is correlated with PTSD symptom severity and duration, such that PTSD patients with high CRP had greater symptom severity and duration than those with low CRP.

    “Michopoulos et al (2015) and Heath et al (2013) reported that CRP concentration was correlated with PTSD symptom severity and duration, such that PTSD patients with high, compared with low, CRP had greater symptom severity and duration (Heath et al, 2013;Michopoulos et al, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Heath et al, 2013 source

      Not checked in the free run.

    • cites Michopoulos et al, 2015 source

      Not checked in the free run.

  • May combine two claims. 22
  • Classified as probably not a substantial claim. 3
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisereasoning

    Psychological stressors increase the risk and severity of mood disorders.

    “There is, therefore, a growing body of clinical studies establishing the association between stressor exposure, inflammation, and mood disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Psychological and/or acute intense stressor exposure in the absence of overt tissue damage can evoke a detectable local and systemic sterile inflammatory response, and DAMPs may have a role.

    “Recently, it has been reported that psychological and/or acute intense stressor exposure in the absence of overt tissue damage can evoke a detectable local and systemic sterile inflammatory response and that DAMPs may have a role (Fleshner, 2013;Frank et al, 2015b;Maslanik et al, 2013;Miller et al, 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Fleshner, 2013 source

      Not checked in the free run.

    • cites Frank et al, 2015b

      Not checked in the free run.

    • cites Maslanik et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1β activation is not strictly caspase-1 dependent in primary microglia, suggesting that inflammasomes may not be necessary for the processing of IL-1β into its mature form in this CNS innate immune cell.

    “Burm et al (2015) have recently demonstrated that IL-1β activation is not strictly caspase-1 dependent in primary microglia, suggesting that inflammasomes may not be necessary for the processing of IL-1β into its mature form in this CNS innate immune cell.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Burm et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cheng et al, 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several studies have characterized inflammasomes in neurons, which are capable of producing IL-1β.

    “several studies have characterized inflammasomes in neurons (de Rivero Vaccari et al, 2009;Kummer et al, 2007), which are capable of producing IL-1β (de Rivero Vaccari et al, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites de Rivero Vaccari et al, 2009 source

      Not checked in the free run.

    • cites Kummer et al, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cheng et al, 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several inflammasomes have been characterized in microglia including NLRP1, NLRP3, and NLRC4.

    “several inflammasomes have been characterized in microglia including NLRP1, NLRP3, and NLRC4 (Walsh et al, 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Walsh et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic unpredictable stress exposure suppressed sucrose intake relative to unstressed controls while increasing the levels of IL-1β mRNA and mature IL-1β protein in the prefrontal cortex.

    “Pan et al (2014) found that CUS exposure suppressed sucrose intake relative to unstressed controls, while increasing the levels of IL-1β mRNA and mature IL-1β protein in the prefrontal cortex (PFC).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pan et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia express PRRs such as TLRs, including TLR2 and TLR4, and TLR ligation potently activates microglia.

    “microglia express PPRs such as TLRs, which include TLR2 and TLR4, and TLR ligation potently activates microglia (Aravalli et al, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aravalli et al, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tailshock increases tissue and blood concentrations of many cytokines and chemokines, and both MAMP and DAMP signals are involved.

    “Tailshock also increases tissue and blood concentrations of many cytokines and chemokines, and both MAMP (derived from the gut bacteria) and DAMP signals are involved (Maslanik et al, 2012b(Maslanik et al, , 2013)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Maslanik et al, 2012b

      Not checked in the free run.

    • cites Maslanik et al, 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several candidate receptors capable of binding DAMPs and MAMPs include TLRs, RAGE, and CD91.

    “there are several candidate receptors capable of binding DAMPs and MAMPs, including TLRs, RAGE, and CD91 (Asea et al, 2002;Calderwood et al, 2007a, b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Asea et al, 2002 source

      Not checked in the free run.

    • cites Calderwood et al, 2007a, b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exposure to acute stress (inescapable tailshock) increases NLRP3 protein in the hippocampus up to 24 h after stress treatment; microglial IL-1β was not increased at that time-point post stress.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weber et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cytokines as well as PAMPs are capable of activating afferent vagal nerve fibers in the periphery, which leads to activation of neural pathways in brain regions implicated in motivation and mood.

    “cytokines as well as PAMPs (eg, LPS) are capable of activating afferent vagal nerve fibers in the periphery, which leads to activation of neural pathways in brain regions implicated in motivation and mood (McCusker and Kelley, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McCusker and Kelley, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microglia can enter a state called 'primed' in which they show phenotypic signs of activation but do not secrete increased cytokines; if stimulated while in this state, they produce and release exaggerated quantities of mediators, including IL-1β.

    “microglia can enter a state called 'primed' (Perry et al, 2007).Here, they show phenotypic signs of activation (eg, upregulated MHCII), but do not secrete increased cytokines.However, if stimulated while in this state, microglia produce and release exaggerated quantities of mediators, including IL-1β.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Perry et al, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1β mediates depressive-like behaviors induced by stress as well as proinflammatory challenges.

    “IL-1β mediates depressive-like behaviors induced by stress as well as proinflammatory challenges, which of course implicates a mechanistic role for inflammasomes because inflammasomes mediate, in large part, the processing and maturation of IL-1β (Jo et al, 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jo et al, 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic unpredictable stress increased NLRP3 protein and mRNA, and mature caspase-1 protein in the prefrontal cortex.

    “CUS also increased NLRP3 protein and mRNA, and mature caspase-1 protein in the PFC.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pan et al, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exposure to an acute stressor (inescapable tailshock) induces HMGB1 in the hippocampus concomitant with increased protein levels of active NF-κB and NLRP3 protein.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weber et al, 2015 source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Exposure of wild-type mice to 2-h immobilization stress every day for 30 consecutive days induced a decrease in sucrose preference and social interaction, and an increase in immobility in the forced swim test.

    “They found that exposure of wild-type mice to immobilization induced a decrease in sucrose preference and social interaction, and an increase in immobility in the forced swim test.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Alcocer-Gomez et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HMGB1 can function as a chemotactic factor and be actively secreted from innate immune cells.

    “HMGB1 can also function as a chemotactic factor and also be actively secreted from innate immune cells (Yang et al, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yang et al, 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    21 days of chronic unpredictable stress resulted in a depressive behavioral phenotype including decreased sucrose preference, which was abrogated in NLRP3 knockout mice.

    “Iwata et al (2015) also found that 21 days of CUS resulted in a depressive behavioral phenotype including decreased sucrose preference, which was abrogated in NLRP3 KO mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Iwata et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    There is some evidence that neuronal damage may occur in major depression, suggesting that DAMPs may also have a role in the pathophysiology of depression.

    “there is some evidence that neuronal damage may occur in major depression (Duman, 2009), suggesting that DAMPs may also have a role in the pathophysiology of depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Duman, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Weber et al, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Initial stress exposure induces the release of HMGB1 in the CNS, which then signals through TLR4 to prime the NLRP3 inflammasome.

    “This set of findings suggests that initial stress exposure induces the release of HMGB1 in the CNS, which then signals through TLR4 to prime the NLRP3 inflammasome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    HMGB1 may serve as both the NLRP3 inflammasome priming stimulus and the activating stimulus.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The NLRP3 inflammasome responds to a broad range of signals, for example, ATP, K+ efflux, β-amyloid, silica, uric acid crystals, and reactive oxygen species.

    “The NLRP3 inflammasome responds to a broad range of signals, for example, ATP, K+ efflux, β-amyloid, silica, uric acid crystals, and reactive oxygen species (ROS)(Elliott and Sutterwala, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Elliott and Sutterwala, 2015 source

      Not checked in the free run.

25 of 25

  • The paper relies on this without support.

    Stress-induced depressive-like behaviors in rodents are a valid model of human mood disorders.

    “The role of inflammasomes in stress-induced depressivelike behaviors has recently become a subject of study.”

  • The authors state this as an assumption.

    Exposure to stressors results in the release of DAMPs within the brain, presumably from damaged or dying neurons.

    “We propose that exposure to stressors results in the release of danger-associated molecular patterns (DAMPs) within the brain, presumably from damaged or dying neurons.”

  • The paper relies on this without support.

    Stress is a well-established trigger of affective dysfunction.

    “In addition, stress is a well-established trigger of affective dysfunction and severe and/or repeated psychological stressor exposure also increases inflammatory proteins in blood and tissues.”

  • The paper relies on this without support.

    Severe and/or repeated psychological stressor exposure increases inflammatory proteins in blood and tissues.

    “In addition, stress is a well-established trigger of affective dysfunction and severe and/or repeated psychological stressor exposure also increases inflammatory proteins in blood and tissues.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Fleshner, M., Frank, M., & Maier, S. F.
Affiliations
University of Colorado Boulder (US)
Corresponding author
Fleshner, Monika
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2016-07-14
Volume
42
Issue
1
Pages
36-45
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2016.125
PMC
PMC5143484
OpenAlex
W2464749518
Semantic Scholar
f1988f7ccf78d3bdba127cd185cae15df050f6ce
Cited by
216
References
101
Citations by year
2026: 6 · 2025: 17 · 2024: 22 · 2023: 32 · 2022: 32 · 2021: 29 · 2020: 33 · 2019: 18 · 2018: 13 · 2017: 12 · 2016: 2
FWCI
0.93
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense
  • Mead Johnson Nutrition
  • National Institutes of Health
  • Office of Naval Research
  • National Institute of Mental Health (R01MH108523)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
major depressive disorder, mood disorders, sterile inflammation, inflammasome, psychological stress, damage-associated molecular patterns, pathogen-associated molecular patterns, microbe-associated molecular patterns, neuroinflammation, inflammatory signaling, therapeutic target
MeSH terms
Animals, Central Nervous System, Humans, Inflammation, Stress, Psychological, Signal Transduction, Microglia, Mood Disorders, Inflammasomes

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review