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Cited by 161Stress Responses and CortisolNeuroinflammation and Neurodegeneration MechanismsTryptophan and brain disorders

Stress-induced glucocorticoids as a neuroendocrine alarm signal of danger

Open access
Frank, Matthew G., Watkins, Linda R., Maier, Steven F.·2013·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2013.02.004PMC PMC5652304
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Abstract

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 that are energy intensive; if unsuccessful, it may be adaptive to inhibit them and conserve energy for physiological adjustments promoting survival.

    “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

    The Introduction says that physically present threats produce defensive behaviors such as fleeing and fighting. It does not specify primitive organisms or defensive reflexes. Its discussion of energy costs concerns immune responses, not reflexes, and it does not say that unsuccessful reflexes are inhibited to conserve energy. (LLM, conf=0.78)

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  • Chronically elevated glucocorticoids can stimulate neuroinflammation by activating microglia, making the process self-perpetuating.

    “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

  • Glucocorticoids and catecholamines are primarily thought to be immunosuppressive and are used therapeutically for this purpose.

    “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

  • Noradrenaline and glucocorticoids mediate the effects of stress on neuroinflammatory processes.

    “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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Authors
Frank, M. G., Watkins, L. R., & Maier, S. F.
Affiliations
University of Colorado Boulder (US)
Corresponding author
Frank, Matthew G.
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2013-10
Volume
33
Pages
1-6
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2013.02.004
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
Licence
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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