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Cited by 578Neuroinflammation and Neurodegeneration MechanismsStress Responses and CortisolTryptophan and brain disorders

Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses

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Frank, Matthew G., Baratta, Michael V., Sprunger, David B., Watkins, Linda R., Maier, Steven F.·2007·Brain Behavior and Immunity
DOI 10.1016/j.bbi.2006.03.005PMC PMC13674783
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Abstract

Prior exposure to a stressor can potentiate CNS pro-inflammatory immune responses to a peripheral immune challenge. However, the neuroimmune substrate(s) mediating this effect has not been determined. The present investigation examined whether microglia serve as this neuroimmune substrate given that microglia are the primary immune effector cell in the CNS. The effect of inescapable shock (IS) on glial activation (MHC II, CD11b, Iba-1, and GFAP) and regulatory markers (CD200) in vivo, and microglia pro-inflammatory responses (interleukin-1beta; IL-1beta) to lipopolysaccharide (LPS) ex vivo, were assessed in rat hippocampus. IS upregulated the microglia activation marker MHC II 24h post-IS, while the astroglia marker GFAP was unaffected. IS also downregulated the neuronal glycoprotein CD200, which functions to hold microglia in a quiescent state. Moreover, IS potentiated the pro-inflammatory response to LPS ex vivo 24h post-IS in isolated hippocampal microglia. Finally, the behavioral controllability of shock was manipulated and the effect of escapable (controllable) shock was comparable to the effect of IS on hippocampal microglia responses to LPS ex vivo. The present results suggest that stress can activate microglia, thereby sensitizing the pro-inflammatory reactivity of microglia to immunogenic stimuli.

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  • Stress-induced brain cytokine increases are transient, but the neuroimmune microenvironment displays a gradual increase in glial activation markers post-stress, which may underlie the sensitized neuroinflammatory response to a subsequent pro-inflammatory challenge.

    “While stress-induced brain cytokine increases are transient and short-lived, the neuroimmune microenvironment displays a gradual increase in glial activation markers post-stress, which may underlie the sensitized neuroinflammatory response that occurs to a subsequent pro-inflammatory challenge, such as drugs of abuse.”

    From Stress- and Glucocorticoid-Induced Priming of Neuroinflammatory Responses: Potential Mechanisms of Stress-Induced Vulnerability to Drugs of Abuse (2011) · cites this paper as Frank et al., 2007

  • Microglia in the stressed brain undergo profound morphological changes, marked by large amoeboid cell bodies and thicker processes.

    “For example, microglia in the stressed brain undergo profound morphological changes, marked by large amoeboid cell bodies and thicker processes (Frank et al, 2007;Wohleb et al, 2011).”

    From Microglia Priming with Aging and Stress (2017) · cites this paper as Frank et al, 2007

  • These morphological alterations were associated with the classical activation profile, characterized by the increased expression of antigen presentation molecule (MHCII), cell surface markers (TLR4 and CD14), and pro-inflammatory cytokines and chemokines (IL-1β, TNFα, IL-6, and CCL2).

    “These morphological alterations were associated with the classical activation profile, characterized by the increased expression of antigen presentation molecule (MHCII), cell surface markers (TLR4 and CD14), and pro-inflammatory cytokines and chemokines (IL-1β, TNFα, IL-6, and CCL2) (Frank et al, 2007;Ramirez et al, 2016;Wohleb et al, 2011).”

    From Microglia Priming with Aging and Stress (2017) · cites this paper as Frank et al, 2007

  • Microglial activation and inflammatory signaling following psychological stress has been reported in mice and rats alike, and has also been recapitulated in other models, such as restraint stress and foot-shock stress.

    “Microglial activation and inflammatory signaling following psychological stress has been reported in mice and rats alike, and has also been recapitulated in other models, such as restraint stress and foot-shock stress (Frank et al, 2007;Hinwood et al, 2012;Kreisel et al, 2014;Tynan et al, 2010;Voorhees et al, 2013).”

    From Microglia Priming with Aging and Stress (2017) · cites this paper as Frank et al, 2007

  • Prior CORT exposure primes cytokine release from microglia ex vivo.

    “and prior CORT exposure primes cytokine release from microglia ex vivo (Frank et al., 2006).”

    From The Stressed CNS: When Glucocorticoids Aggravate Inflammation (2009) · cites this paper as Frank et al., 2006

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Authors
Frank, M. G., Baratta, M. V., Sprunger, D. B., 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
2007-01
Volume
21
Issue
1
Pages
47-59
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2006.03.005
PMC
PMC13674783
OpenAlex
W2095547457
Cited by
578
References
51
Citations by year
2026: 14 · 2025: 23 · 2024: 27 · 2023: 26 · 2022: 29 · 2021: 40 · 2020: 37 · 2019: 32 · 2018: 40 · 2017: 39 · 2016: 41 · 2015: 37 · 2014: 31 · 2013: 36 · 2012: 35
FWCI
9.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
National Institute of Mental Health (F31MH075213)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
microglia, neuroimmune interactions, inescapable shock, hippocampus, glial activation, CD200, MHC class II, IL-1β, lipopolysaccharide, inflammatory cytokines, escapable shock, astrocytes
MeSH terms
Animals, Hippocampus, Histocompatibility Antigens, Immunohistochemistry, Interleukins, Lipopolysaccharides, Macrophages, Male, RNA, Messenger, Stress, Psychological, Rats, Sprague-Dawley, Microglia, Gene Expression Profiling, Rats

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