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Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger
Open accessAbstract
A considerable number of studies demonstrate that acute and chronic stressors prime CNS innate immune responses to subsequent pro-inflammatory challenges and that glucocorticoids mediate, in part, stress-induced sensitization of pro-inflammatory immune responses. Here, we explore the notion that GCs produce a persisting sensitization of CNS innate immune effectors (e.g. microglia) so that they will generate a potentiated pro-inflammatory response after the GC rise has dissipated, thereby enhancing the sickness response to infection or injury and maximizing the animal's ability to neutralize danger. The stress-induced GC response is conceptualized here as an neuroendocrine warning signal or alarmin to the innate immune system, which prepares or sensitizes the innate immune response to potential danger. Thus, a new understanding of the stress response and its function (priming CNS innate immune responses to infection or injury during a fight/flight emergency) would be suggested.
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“In primitive organisms threats engage defensive reflexes (Walters & Erickson, 1986).”
From Learned helplessness at fifty: Insights from neuroscience. (2016) · cites this paper as Frank, Watkins, & Maier, 2013
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“This process can become self-perpetuating because chronically elevated glucocorticoids can stimulate production of neuroinflammation by activating microglia (Frank et al., 2013; Nair and Bonneau, 2006), the resident immune cells of the brain.”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Frank et al., 2013
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“However, the well-studied mediators of stress physiology, glucocorticoids and catecholamines, are primarily thought to be immunosuppressive (Russell and Lightman, 2019) and used therapeutically for this purpose, creating a paradox that many have tried to resolve for over 30 years (Frank et al., 2013; Munck et al., 1984).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Frank et al., 2013
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“A number of mediators of the stress response, most notably noradrenaline and glucocorticoids, have been found to mediate the effects of stress on neuroinflammatory processes (Frank et al, 2013;Wohleb et al, 2011).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Frank et al, 2013
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Metadata
- Authors
- Frank, M. G., Watkins, L. R., & Maier, S. F.
- Affiliations
- University of Colorado Boulder (US)
- Corresponding author
- Frank, Matthew G.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 33
- Pages
- 1-6
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5652304
- OpenAlex
- W2025373842
- Cited by
- 160
- References
- 67
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 12 · 2021: 13 · 2020: 18 · 2019: 13 · 2018: 18 · 2017: 14 · 2016: 17 · 2015: 18 · 2014: 9 · 2013: 4
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Drug Abuse (F32DA015591)
- National Institute of Dental and Craniofacial Research (R01DE021966)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- microglia, alarmins, threat detection, stress response, glucocorticoid feedback
- MeSH terms
- Animals, Brain, Central Nervous System, Disease Models, Animal, Glucocorticoids, Humans, Immunity, Innate, Neuroimmunomodulation, Signal Transduction, Oxidative Stress
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