Neuroinflammatory Responses in Stress and Glucocorticoid Regulation

Psychological or physiological stress engages the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system, releasing glucocorticoids and catecholamines that shape immune activity in the brain. Although glucocorticoids are traditionally viewed as anti-inflammatory, evidence increasingly shows that their effects depend on dose, exposure duration and cellular context, sometimes potentiating pro-inflammatory cascades. Microglia and astrocytes respond to stress-induced signals by altering morphology, proliferating and producing cytokines such as interleukin-1 and interleukin-6. These changes are most pronounced in the hippocampus, amygdala and hypothalamus, regions governing mood, cognition and homeostasis. Chronic stress can disrupt adult neurogenesis, particularly in the hippocampus and newly recognised hypothalamic stem cell niches, with inflammation driving maladaptive plasticity. Reciprocal interactions between glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) pathways in microglia further modulate nuclear factor-κB activity and inflammasome assembly. Clinically, these adaptations are implicated in depression, anxiety, cognitive impairment and neurodegenerative diseases. Understanding how stress hormones both suppress and exacerbate neuroinflammation offers routes to intervention, from selective GR modulators to cytokine-targeting agents, and underscores the global importance of managing stress to protect brain health.

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Neuroinflammatory Responses in Stress and Glucocorticoid Regulation publication trend

The graph below shows the total number of articles in neuroinflammatory responses in stress and glucocorticoid regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: resident immune cells of the central nervous system involved in surveillance and inflammatory responses.

Astrocyte: glial cell type that supports neuronal function, contributes to neurotransmitter regulation and can become reactive during inflammation.

HPA axis: hypothalamic–pituitary–adrenal axis, a central stress response system regulating release of corticotropin-releasing hormone, adrenocorticotropic hormone and glucocorticoids.

Glucocorticoid: steroid hormone produced by the adrenal cortex in response to stress, acting via intracellular receptors with complex immunomodulatory effects.

Neuroinflammation: the production of pro-inflammatory mediators within the brain, typically involving activation of microglia and astrocytes.

Cytokine: small signalling proteins such as interleukins and tumour necrosis factors that mediate immune and inflammatory processes.

References

1. IL-1 Mediates Chronic Stress-Induced Hyperalgesia Accompanied by Microglia and Astroglia Morphological Changes in Pain-Related Brain Regions in Mice. International Journal of Molecular Sciences (2023).
2. Ouabain Reverts CUS-Induced Disruption of the HPA Axis and Avoids Long-Term Spatial Memory Deficits. Biomedicines (2023).
3. New insights into hypothalamic neurogenesis disruption after acute and intense stress: implications for microglia and inflammation. Frontiers in Neuroscience (2023).
4. The Pro-inflammatory Effects of Glucocorticoids in the Brain. Frontiers in Endocrinology (2016).
5. The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain. Frontiers in Immunology (2014).
6. Stress and brain immunity: Microglial homeostasis through hypothalamus-pituitary-adrenal gland axis and sympathetic nervous system. Brain Behavior & Immunity - Health (2020).
7. Mineralocorticoid and glucocorticoid receptors differentially regulate NF-kappaB activity and pro-inflammatory cytokine production in murine BV-2 microglial cells. Journal of Neuroinflammation (2012).