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Cited by 582Tryptophan and brain disordersStress Responses and CortisolInflammasome and immune disorders

The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses

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Iwata, Masaaki, Ota, Kristie T., Duman, Ronald S.·2013·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2012.12.008PMC PMC4426992
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Abstract

Stress is a common occurrence in everyday life and repeated or traumatic stress can be a precipitating factor for illnesses of the central nervous system, as well as peripheral organ systems. For example, severe or long-term psychological stress can not only induce depression, a leading illness worldwide, but can also cause psychosomatic diseases such as asthma and rheumatoid arthritis. Related key questions include how psychological stress influences both brain and peripheral systems, and what detection mechanisms underlie these effects? A clue is provided by the discovery of the pathways underlying the responses to host "danger" substances that cause systemic diseases, but can also contribute to depression. The inflammasome is a protein complex that can detect diverse danger signals and produce the accompanying immune-inflammatory reactions. Interestingly, the inflammasome can detect not only pathogen-associated molecules, but also cell damage-associated molecules such as ATP. Here, we propose a new inflammasome hypothesis of depression and related comorbid systemic illnesses. According to this hypothesis, the inflammasome is a central mediator by which psychological and physical stressors can contribute to the development of depression, and as well as a bridge to systemic diseases. This hypothesis includes an explanation for how psychological stress can influence systemic diseases, and conversely how systemic diseases can lead to psychiatric illnesses. The evidence suggests that the inflammasome may be a new target for the development of treatments for depression, as well as psychosomatic and somato-psycho diseases.

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  • Stress exposure releases danger-associated molecular patterns such as heat-shock proteins and ATP, inducing a NLRP3 inflammasome response that leads to release of IL-1β and other cytokines.

    “On a cellular level, the release of danger-associated molecular patterns, such as heat-shock proteins and adenosine triphosphate, in response to stress exposure induces a NLRP3 inflammasome response that leads to the release of IL-1β and other cytokines (Iwata et al, 2013;Maslanik et al, 2013).”

    From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Iwata et al, 2013

    Section 5.5 reports preliminary, unpublished findings that stress increases hippocampal ATP, followed by P2X7-dependent elevation of IL-1β and subsequent release of TNFα and IL-6. Sections 3 and 4 link ATP–P2X7 signaling to NLRP3 processing of IL-1β and describe NLRP3 recognition of damage-associated molecules. Our copy does not establish that stress releases heat-shock proteins, and the cited stress findings are preliminary rather than an established general response. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Inflammasomes may represent a crucial immunological interface between stress and inflammation.

    “recent focus has been shifted towards inflammasomes, which may represent a crucial immunological interface between stress and inflammation40”

    From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [40]

  • The canonical stress pathway, involving the hypothalamus-pituitary-adrenal axis, exhibits dysregulation in depression associated with increased cortisol and subsequent neuronal atrophy in the hippocampus and mPFC.

    “The canonical stress pathway, involving the hypothalamus–pituitary–adrenal axis, exhibits dysregulation in depression (for review ref. 155) associated with increased cortisol156 and subsequent neuronal atrophy in the hippocampus157 and mPFC158.”

    From Paying attention to attention in depression (2019) · cites this paper as [155]

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Authors
Iwata, M., Ota, K. T., & Duman, R. S.
Affiliations
Yale University (US)
Corresponding author
Duman, Ronald S.
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2013-07
Volume
31
Pages
105-114
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2012.12.008
PMC
PMC4426992
OpenAlex
W1964744961
Cited by
580
References
135
Citations by year
2026: 23 · 2025: 27 · 2024: 49 · 2023: 41 · 2022: 56 · 2021: 58 · 2020: 56 · 2019: 44 · 2018: 55 · 2017: 58 · 2016: 41 · 2015: 31 · 2014: 21 · 2013: 17
FWCI
6.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (R01MH045481)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
inflammasome, psychological stress, depression, psychosomatic disorders, asthma, rheumatoid arthritis, damage-associated molecular patterns, ATP, neuroinflammation, systemic disease, comorbidities
MeSH terms
Depressive Disorder, Humans, Inflammation, Models, Theoretical, Stress, Psychological

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