From inflammation to sickness and depression: when the immune system subjugates the brain

• Published in: Nature reviews. Neuroscience Vol. 9; no. 1; pp. 46 - 56
• Main Authors: Dantzer, Robert, O'Connor, Jason C, Freund, Gregory G, Johnson, Rodney W, Kelley, Keith W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2008; Nature Publishing Group
• Subjects: Adult and adolescent clinical studies; Animal Genetics and Genomics; Animals; Bacterial infections; Behavioral Sciences; Biological and medical sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Blood vessels; Brain; Brain - physiopathology; Cytokines; Cytokines - metabolism; Depression; Depression - etiology; Depression - metabolism; Depression, Mental; Diagnosis; Disease - etiology; Disease - psychology; Fundamental and applied biological sciences. Psychology; General aspects. Models. Methods; Health aspects; Humans; Hydrocarbons; Immune system; Immune System - physiopathology; Infections; Inflammation; Inflammation - complications; Inflammation - immunology; Inflammation - metabolism; Inflammation - physiopathology; Medical sciences; Mental depression; Mood disorders; Neurobiology; Neurosciences; Pathogens; Physiological aspects; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; review-article; Risk factors; Tumor necrosis factor-TNF; Vertebrates: nervous system and sense organs; United States; United States > US; Illinois; Mood disorder; Immunopathology; Prevalence; Central nervous system; Cytokine; Depression; Autoimmune disease; Review; Malignant tumor; Psychosocial factor; Encephalon; Risk factor; Cancer; Immune system
• DOI: 10.1038/nrn2297
• ISSN: 1471-003X; 1471-0048

Key Points Infections cause people to become sick and change their behaviour. They develop fever, sleep poorly, eat less, experience difficulty with memory and learning, withdraw socially and complain of pain and fatigue. Glial and macrophage-like cells in the brain respond to peripheral infection by synthesizing the same pro-inflammatory and anti-inflammatory cytokines as those produced by leukocytes. Several immune-to-brain communication pathways act in parallel; these include a fast neural afferent pathway and a slower humoral pathway that requires a relay in circumventricular organs and the brain vasculature. The predominant pro-inflammatory cytokines that cause behavioural signs of sickness are interleukin-1β and tumour necrosis factor-α (TNF-α). Inflammation and sickness place a burden on working memory by reducing the ability of the short-term memory register to process environmental stimuli. This effect is likely to be responsible for the alterations in cognition that are caused by inflammation. Sickness is as normal to infection as the fear response is to a threatening predator. Its purpose is to promote survival of the organism. If infections do not resolve and peripheral inflammation continues unabated, clinical depression can develop over a background of sickness behaviour. A mechanism for inflammation-associated depression is shunting of tryptophan away from serotonin synthesis, by activation of indoleamine 2,3 dioxygenase (IDO), an enzyme that is predominantly synthesized by myeloid cells, such as macrophages and microglia. IDO activity is stimulated mainly by TNF-α and interferon-γ. This leads to the production of neuroactive tryptophan metabolites that can induce depression-like behaviour by altering glutamatergic neurotransmission. Ageing, obesity and other conditions associated with chronic inflammation increase the risk of development and persistence of inflammation-associated sickness and depression. Cytokines, produced in response to peripheral infections, act in the brain to cause sickness behaviour. Dantzer and colleagues consider the intriguing hypothesis that prolonged immune signalling in the brain can cause symptoms of depression and discuss the mechanisms that might underlie this phenomenon. In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.