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The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses
Open accessAbstract
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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“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
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“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]
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“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.”
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Metadata
- Authors
- Iwata, M., Ota, K. T., & Duman, R. S.
- Affiliations
- Yale University (US)
- Corresponding author
- Duman, Ronald S.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 31
- Pages
- 105-114
- ISSN
- 0889-1591 (ISSN-L)
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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