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

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.

Abstract

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.

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Figure 1: Pathways that transduce immune signals from the periphery to the brain.
Figure 2: Increased brain cytokine signalling impairs learning and memory.
Figure 3: LPs-increased depression-like behaviour in mice.
Figure 4: Depression as a consequence of decompensation of the mechanisms that regulate sickness.

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Acknowledgements

The authors' work described here is supported by grants from the National Institute of Mental Health (NIMH), the National Institute on Aging (NIA) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). R.D. (R01 MH 079829 and R01 MH 71349), K.W.K. (R01 MH 51569 and R01 AG 029573) R.W.J. (R01 AG 023580, AG 0616710, MH 069148 and R21 DA 024443) and G.G.F (R01 DK 064862). The authors thank R. -M. Bluthe, N. Castanon, S. Laye, P. Parnet, J. P. Konsman, J. Lestage, L. Capuron, C. Dantzer and their Ph.D. students for their valuable contribution to many of the results and concepts presented in this Review.

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Glossary

Accessory immune cells

Cells such as macrophages and dendritic cells that are required for, but do not actually mediate, adaptive immune responses of T and B lymphocytes.

Motivational state

A central state that re-organizes perception and action.

Inflammation

A response of tissues to injury or irritation that is characterized by pain, swelling, redness and heat.

Physical illness

An infectious, autoimmune or oncogenic disease in which physical rather than psychological symptoms of the diseased tissue or organ predominate.

Choroid plexus

A capillary bed that is covered by transporting ependymal cells and that protrudes into the cerebral ventricles. The ependymal cells are responsible for producing cerebral spinal fluid.

Meninges

The three protective layers of tissue that surround the brain and spinal cord.

Prostaglandin

Cellular communication molecule synthesized from arachidonic acid. Specific compounds are designated by adding a letter to indicate the type of substituents found on the hydrocarbon skeleton and a subscript to indicate the number of double bonds in the hydrocarbon skeleton.

Vagal nerve

The 10th pair of cranial nerves that innervates the pharynx, larynx and visceral organs. It contains more afferent than efferent nerve fibres and projects from the medulla oblongata in the brain stem to the colon.

Toll-like receptor

Highly conserved membrane spanning receptor that recognizes pathogenic molecules that are distinct from host antigens (collectively referred to as pathogen-associated molecular patterns).

Circumventricular organs

Structures that surround the brain ventricles and are devoid of a functional blood–brain barrier because of fenestrated capillaries.

Blood–brain barrier

A series of structures that limit the penetration and diffusion of circulating water-soluble substances into the brain and include tight junctions between endothelial cells of brain capillaries, a dense network of astrocytes, a reduced volume of extracellular milieu and efflux pumps.

Volume diffusion

A form of neurotransmission that involves the diffusion in the extracellular space of neurotransmitters that are normally released from neurons. Volume diffusion permits neurotransmitters and cytokines to reach extrasynaptic receptors.

Parenchyma

The tissue of an organ, in this case the brain, that supports its functions and is distinct from supporting and connective tissue.

Anti-inflammatory cytokines

Together with specific cytokine inhibitors and soluble cytokine receptors, these are immunoregulatory molecules that down-regulate the pro-inflammatory cytokine response.

Innate immune system

Part of the immune system that is responsible for natural immunity and is geared toward efficiently recognizing pathogenic molecules independently of any prior exposure.

Acute-phase response

The reaction that develops in response to an injury. It is mediated by pro-inflammatory cytokines and is characterized by a local response (inflammation) and a systemic component, which includes production of acute phase proteins by hepatocytes, fever and profound changes in lipid, protein and carbohydrate metabolism.

Neurovegetative

This term refers to phenomena that are visceral and controlled by the autonomic nervous system. In the case of depression, neurovegetative symptoms include sleep disturbances, change in appetite and decreased energy.

Depression-like behaviour

Behaviour displayed by laboratory animals that mimics some features of clinical depression. These include, among others, helplessness and anhedonia. Depression-like behaviour is normally alleviated by antidepressant drugs.

Glucocorticoid receptor resistance

This occurs despite normal or excessive concentrations of glucocorticoids. It is sometimes caused by loss-of-function mutations in the glucocorticoid receptor and, more commonly, by events that occur during chronic inflammation, ultimately leading to a reduction in the ability of glucocorticoids to translocate into the nucleus.

Psychomotor retardation

A generalized slowing of physical and mental activity, frequently occurring as a symptom of severe depression.

Co-morbidity

The presence of one or more diseases in addition to a primary disease.

Illness behaviour

In health psychology, illness behaviour refers to any behaviour undertaken by an individual who feels ill in order to relieve that experience and to better understand the meaning of disease symptoms. It is profoundly influenced by the social context and psychological factors, and manifests itself by denial or amplification of symptoms, attributional processes, a search for medical information, decisions for entering or leaving the health care system, and adherence to treatment.

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Dantzer, R., O'Connor, J., Freund, G. et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9, 46–56 (2008). https://doi.org/10.1038/nrn2297

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