Neuroimmune Interactions in Stress and Affect

Stress engages neuroendocrine pathways that alter both central and peripheral immune responses, forging a bidirectional dialogue between brain and body. In the central nervous system, microglia become activated under chronic stress, releasing pro-inflammatory mediators and driving synaptic remodelling in regions such as the prefrontal cortex and hippocampus. Concurrently, peripheral monocytes can be primed and recruited across a compromised blood–brain barrier, releasing enzymes that reshape extracellular matrices and modify neural activity in limbic structures. Adaptive immune elements may also contribute via stress-induced autoantibodies that target brain antigens, promoting vascular inflammation and behavioural disturbances. Together, these mechanisms underlie anxiety, anhedonia and cognitive deficits but also implicate resilience pathways. Elucidating the molecular mediators and circuit-specific interactions offers novel targets for intervention in stress-related affective disorders with global relevance.

Research from Nature Portfolio

Recent studies have identified matrix metalloproteinase 8 derived from circulating monocytes as a key mediator of stress susceptibility, infiltrating the nucleus accumbens, reshaping extracellular spaces and driving social avoidance via altered neurophysiology. In addition, transcriptomic profiling of microglia in stress-susceptible animals has revealed inflammatory signatures linked to oxidative stress and blood–brain barrier breakdown, suggesting that microglial activation and vascular disruption collaborate to precipitate affective disturbances.

Neuroimmune Interactions in Stress and Affect publication trend

The graph below shows the total number of articles in neuroimmune interactions in stress and affect across all publications each year (not limited to Nature Index journals).

Technical terms

Microglia: Resident innate immune cells of the central nervous system involved in surveillance, cytokine release and synaptic remodelling.

Monocyte: A type of peripheral white blood cell that can traffic into the brain and differentiate into macrophage-like cells under stress.

Blood–brain barrier: A selective vascular interface that normally restricts entry of peripheral factors into the brain parenchyma.

Cytokine: Small protein mediators released by immune and neural cells to regulate inflammation and cell-to-cell communication.

Autoantibody: An antibody generated against one’s own neural antigens, potentially contributing to neuroinflammation and behavioural changes.

Interleukin-1 receptor type 1: The principal receptor for interleukin-1β on neurons and glia, mediating inflammatory signalling in stress circuits.

References

1. Circulating myeloid-derived MMP8 in stress susceptibility and depression. Nature (2024).
2. Enhanced fear memory after social defeat in mice is dependent on interleukin-1 receptor signaling in glutamatergic neurons. Molecular Psychiatry (2024).
3. Social stress induces autoimmune responses against the brain. Proceedings of the National Academy of Sciences of the United States of America (2023).
4. The activation of the piriform cortex to lateral septum pathway during chronic social defeat stress is crucial for the induction of behavioral disturbance in mice. Neuropsychopharmacology (2024).
5. Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility. Scientific Reports (2018).