The role of inflammation in depression: from evolutionary imperative to modern treatment target

• Published in: Nature reviews. Immunology Vol. 16; no. 1; pp. 22 - 34
• Main Authors: Miller, Andrew H., Raison, Charles L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2016; Nature Publishing Group
• Subjects: 631/250/2152; 631/250/256; 631/250/262; 631/378/1689/1414; Adaptive Immunity - immunology; Biomedicine; Brain - immunology; Brain - pathology; Care and treatment; Cytokines - immunology; Depression - psychology; Depression, Mental; Humans; Immune response; Immune system; Immunity, Innate - immunology; Immunology; Inflammasomes - immunology; Inflammation; Inflammation - immunology; Inflammation - psychology; Medical research; Medicine, Experimental; Mental depression; Neurotransmitter Agents - metabolism; Observations; Physiological aspects; Predators; review-article; Signal Transduction - immunology; T-Lymphocytes - immunology
• ISSN: 1474-1733; 1474-1741; 1474-1741
• DOI: 10.1038/nri.2015.5

Key Points 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. In this Review, the authors relate the growing appreciation of the neuroimmune circuits that link inflammatory and immune responses with depressive behaviours. They explore the evolutionary basis of this neuroimmune link and discuss how a better understanding of these pathways may lead to new therapies that treat depression by targeting the immune system. 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.