Across evolutionary time, inflammatory responses and depressive symptoms were part of an integrated adaptive response to pathogens that facilitated fighting infection, healing wounds and avoiding subsequent pathogen exposure in the pathogen-rich environments in which humans evolved. In the more sanitary environments of the modern world, the relationship between inflammatory pathways and the brain may drive depression and contribute to non-response to antidepressant medication.
Increased levels of inflammatory cytokines and induction of their signalling pathways as well as activation of different immune cell subsets has been detected in the brain and peripheral blood of a subgroup of patients with depression. C-reactive protein (CRP), tumour necrosis factor, interleukin-1β (IL-1β) and IL-6 appear to be the most reliably elevated inflammatory markers in the peripheral blood of subjects with depression.
Activation of the inflammasome by stress-induced, non-pathogenic stimuli, including damage-associated molecular patterns as well as microbial-associated molecular patterns elaborated from the gut microbiome, may drive peripheral inflammatory responses, which are then transmitted to the brain by trafficking of activated monocytes.
Inflammation impacts several neurotransmitter systems in the brain, including serotonin, dopamine and glutamate pathways, as well as the kynurenine pathway, which generates the neurotoxic metabolite quinolinic acid. Neuroimaging studies have demonstrated that disruption of neurotransmitter pathways is associated with inflammation-induced alterations in brain circuits that mediate motivation and motor activity as well as anxiety, arousal and alarm.
Activation of effector T cells during stress can prevent the development of depressive- and anxiety-like behaviour in mice. These effects may be mediated by the trafficking of effector T cells to the meningeal space where they produce IL-4, which supports anti-inflammatory responses while also stimulating the production of growth factors in the brain that support neural plasticity and resilience.
Studies in depression suggest that inflammatory biomarkers, such as CRP, can be used to enrich samples for anti-inflammatory clinical trials for depression that target inflammation-related symptoms such as anhedonia and anxiety, thereby supporting intelligent trial design. Though still in development, imaging of neuroinflammation will help establish a 'target' in the brain to further facilitate the testing of anti-inflammatory therapies for depression.
Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.
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The authors declare no competing financial interests.
Members of the same species.
- Sickness behaviour
An adaptive response to illness, often precipitated by infection, that includes social withdrawal, decreased appetite, lethargy, impaired concentration, depressed mood, irritability, muscle aches and pain, and fever. This syndrome is believed to prioritize shifting of energy resources to fighting infection and wound healing.
A lack of interest in usually pleasurable activities that represents a decrease in motivation, which can either represent a decrease in the response to reward or in the willingness to expend effort to obtain reward.
- Major depressive disorder
A clinical syndrome of depression characterized by the primary symptoms of depressed mood and anhedonia, and diagnosed using criteria set forth by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
- Social defeat stress
A model of depression that entails repeated exposure to a conspecific animal screened for aggressive behaviour. The animals are placed together in the same cage where they are exposed to brief bouts of defeat lasting 5–10 minutes daily typically for 6–10 days.
- Myeloid-derived suppressor cells
A heterogeneous population of cells of myeloid origin that rapidly expands during inflammation and can potently suppress T cell responses. They are now being explored as potential therapeutic targets to inhibit immune responses in autoimmune disease or transplant rejection.
- Cytokine hypothesis of depression
A theoretical framework that suggests that cytokines have a primary role in alterations of neurotransmitter metabolism, neuroendocrine function, neuroplasticity, neurocircuitry and behaviour in a subgroup of patients with depression and increased inflammation.
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Miller, A., Raison, C. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 16, 22–34 (2016). https://doi.org/10.1038/nri.2015.5
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