Chronic Stress Effects on Immune Function

Chronic stress exerts profound and multifaceted impacts on immune function, orchestrated through enduring activation of stress response systems and resultant alterations in cellular and molecular pathways. Sustained engagement of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system promotes persistent elevation of glucocorticoids and catecholamines, which in turn modulate leukocyte distribution, suppress lymphocyte proliferation, and skew cytokine profiles towards pro‐inflammatory or immunosuppressive states. Structural changes in primary and secondary lymphoid organs, including thymic involution and splenic remodelling, accompany shifts in myeloid and lymphoid cell populations, leading to impaired host defence and increased susceptibility to infection, autoimmunity and tumour progression. Moreover, chronic stress interacts with environmental factors—such as the composition of immunoregulatory microbiota—to influence systemic inflammation and resilience. Together, these alterations underpin the global significance of stress‐induced immune dysregulation, with practical implications for preventative strategies and therapeutic interventions aimed at restoring immunological balance.

Research from Nature Portfolio

Recent studies have elucidated the cellular mechanisms by which sustained psychosocial stress impairs immune regulation within the spleen. In rodent models of chronic social stress, persistent exposure to subordinate housing conditions was shown to induce glucocorticoid resistance in splenic immune cells, characterised by reduced sensitivity of lipopolysaccharide‐stimulated splenocytes to cortisol. This resistance was found to depend on both wounding during social conflict and the presence of CD11b‐positive myeloid cells. Importantly, spleen cell activation occurred independently of physical injury, whereas development of glucocorticoid resistance required both tissue trauma and specific immune cell subsets. These findings reveal how stress‐related immune dysregulation arises from the interplay between behavioural stressors, physical injury and innate immune components.

Research from all publishers

A study of psychological stress and intestinal health demonstrated that chronic elevation of corticosterone directly impaired the function of intestinal stem cells by upregulating FKBP5, leading to reduced proliferative capacity and increased susceptibility to colitis. This work highlights a specific brain–gut axis mechanism through which stress exacerbates inflammatory disease.

Research into the ‘Old Friends’ hypothesis has provided evidence that diminished exposure to immunoregulatory microorganisms in modern environments may predispose individuals to heightened inflammation under chronic stress. Restoration of contact with such microbial species has been proposed as a strategy to enhance stress resilience by promoting regulatory immune pathways and attenuating pro‐inflammatory responses.

Conceptual frameworks have emphasised chronic mild inflammation as a unifying pathway in stress‐related disease. Persistent low‐grade inflammation, driven by prolonged activation of stress systems, has been implicated in cardiovascular, metabolic and neuropsychiatric disorders, underscoring the importance of anti‐inflammatory approaches in prevention and treatment.

Chronic Stress Effects on Immune Function publication trend

The graph below shows the total number of articles in chronic stress effects on immune function across all publications each year (not limited to Nature Index journals).

Technical terms

Hypothalamic–pituitary–adrenal (HPA) axis: The central neuroendocrine system that coordinates the release of adrenocorticotropic hormone from the pituitary and cortisol (or corticosterone) from the adrenal cortex in response to stress.

Glucocorticoid resistance: A condition in which immune cells become less responsive to the anti‐inflammatory effects of glucocorticoid hormones, leading to dysregulated inflammatory responses.

Corticosterone: The principal glucocorticoid hormone in rodents, analogous to cortisol in humans, which mediates many of the physiological effects of stress on immune and metabolic processes.

Cytokines: Signalling proteins secreted by immune cells that regulate inflammation, cell growth and communication within the immune system.

Immunoregulatory microorganisms (‘Old Friends’): Commensal and environmental microbes that have co‐evolved with humans to modulate immune responses and promote regulatory pathways, contributing to stress resilience.

References

1. Psychological stress-induced systemic corticosterone directly sabotages intestinal stem cells and exacerbates colitis. Cell Discovery (2025).
2. Inflammation: The Common Pathway of Stress-Related Diseases. Frontiers in Human Neuroscience (2017).
3. Old Friends, immunoregulation, and stress resilience. Pflügers Archiv - European Journal of Physiology (2018).
4. Splenic glucocorticoid resistance following psychosocial stress requires physical injury. Scientific Reports (2017).