From inflammation to sickness and depression: when the immune system subjugates the brain
Top Cited Papers
- 1 January 2008
- journal article
- review article
- Published by Springer Science and Business Media LLC in Nature Reviews Neuroscience
- Vol. 9 (1), 46-56
- https://doi.org/10.1038/nrn2297
Abstract
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.Keywords
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