Neuroinflammatory Mechanisms in Mood and Psychotic Disorders

Accumulating evidence indicates that dysregulated immune signalling and inflammation play central roles in the pathogenesis of depression, bipolar disorder and schizophrenia. Peripheral immune activation, characterised by elevated pro-inflammatory cytokines and acute-phase proteins, can breach the blood–brain barrier and engage microglial and astrocytic responses in key limbic and cortical circuits. Activated microglia release neurotoxic mediators and alter synaptic pruning, while astrocyte dysfunction impairs metabolic support and neurotransmitter clearance. Concurrently, the kynurenine pathway diverts tryptophan metabolism towards neurotoxic metabolites that disrupt glutamatergic and monoaminergic transmission. Early-life adversity and chronic psychosocial stress prime the neuroimmune axis, lowering the threshold for subsequent inflammatory insults. This interplay between systemic and central immunity manifests clinically as mood dysregulation, cognitive impairment and, in susceptible individuals, psychotic symptoms. Therapeutic strategies targeting inflammatory mediators, blood–brain barrier integrity and neuroimmune modulators hold promise for stratified interventions and novel drug development.

Research from Nature Portfolio

Recent studies have identified a direct communication axis between specific brain nuclei and peripheral lymphoid organs that modulates stress-induced emotional responses. Experiments in rodent models demonstrated that glutamatergic neurons in the red nucleus regulate the secretion of the chemokine CCL5 from cervical lymph nodes under restraint stress. Inhibition of this pathway exacerbates anxiety-like behaviour and elevates systemic CCL5, whereas its activation attenuates both behavioural and immune responses. These findings reveal an anatomically defined brain–lymph node circuit that governs neuroimmune interactions and suggest new targets for modulating inflammation-associated affective disturbances.

Neuroinflammatory Mechanisms in Mood and Psychotic Disorders publication trend

The graph below shows the total number of articles in neuroinflammatory mechanisms in mood and psychotic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Cytokine: A small protein secreted by immune cells that modulates inflammation and cell signalling within the central nervous system and periphery.

Chemokine: A subtype of cytokine that directs the migration of immune cells to sites of inflammation or tissue injury.

Microglia: Resident immune cells of the brain that survey the neural environment, clear debris and regulate synaptic connectivity under physiological and pathological conditions.

Blood–brain barrier: A selective endothelial interface that regulates molecular and cellular trafficking between the bloodstream and neural tissue.

Kynurenine pathway: A metabolic cascade converting tryptophan into neuroactive metabolites, some of which exert neurotoxic or neuromodulatory effects on glutamate receptors.

References

1. Psychoneuroimmunology: An Introduction to Immune-to-Brain Communication and Its Implications for Clinical Psychology. Annual Review of Clinical Psychology (2023).
2. Stress-induced red nucleus attenuation induces anxiety-like behavior and lymph node CCL5 secretion. Nature Communications (2023).
3. Trajectories of Inflammation in Youth and Risk of Mental and Cardiometabolic Disorders in Adulthood. JAMA Psychiatry (2024).
4. Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study. JAMA Psychiatry (2017).