The findings described here indicate that we are starting to understand why we feel sick and behave accordingly when we are ill. We now also recognize that inflammation is an important biological event that increases the risk of occurrence of major depressive episodes, much like the more traditional psychosocial factors such as the death of a loved one. Importantly, the rapid increase in knowledge about immune-to-brain communication must be translated into clinical practice.
In the clinic, symptoms of sickness (for example, fatigue, reduced appetite, sleep disorders, altered mood and cognition) are well known to have a negative impact on the quality of life of patients with chronic inflammatory disorders, but not much can be done to alleviate these symptoms. Controlled studies are necessary to validate the putative beneficial value of various nutriments and intervention (for example, physical exercise) on the symptoms of sickness. Such studies can now be carried out at the preclinical and clinical levels by not only evaluating clinically relevant end-points (for example, alleviation of fatigue or depressed mood) but also by taking into account intermediate mechanisms using biomarkers of inflammation. If confirmed in the clinic, the efficacy of compounds targeting IDO and inflammatory mediators for the alleviation of symptoms of depression will open new opportunities for drug development. However, as such compounds have the potential to compromise resistance to infection, targets in the brain should be preferred over peripheral ones.
At the basic science level, it must be recognized that research into cytokine-induced sickness behaviour is still in its infancy. For example, the neurobiological mechanisms underlying the behavioural effects of pro-inflammatory cytokines have rarely been investigated in enough detail to be able to relate a given behavioural effect of a cytokine to a specific action in a well-defined area(s) in the brain29
. Micropharmacology experiments that use both in vivo
dialysis and approaches that target inflammatory mediators in specific brain areas need to be implemented in order to define the cause–effect relationships more clearly. The field will also benefit from newly-developed technologies that use approaches based on genomic biology. Furthermore, as behaviour has a temporal component, techniques that enable continuous monitoring of biologic phenomena have considerable advantages over techniques that require euthanasia of animals at specific time points. In particular, optical recording of either neuronal activity in vivo
using voltage-sensitive dye imaging84
or activation patterns of molecules labelled with genetically encoded, green-fluorescent-protein-based indicators (for example, COX2 (REF. 85
) and IDO86
) could enlighten our understanding of the neural basis of cytokine-induced sickness and depression-like behaviour.
Very little is known about the contribution of immune-cell trafficking in the brain to the activation of pro-inflammatory cytokine signalling and its behavioural consequences, even though this is likely to be important in CNS diseases. For example, depression is a highly prevalent co-morbid condition in multiple sclerosis87
. This autoimmune neuroinflammatory disease can be modelled in rodents by a condition known as experimental allergic encephalomyelitis (EAE) that is associated with clear signs of sickness and depression-like behaviour88,89
. Elucidation of the temporal dynamics of immune cell recruitment in the brains of mice with EAE90,91
provides a valuable tool for studying the contribution of leukocyte trafficking to the activation of cytokine signalling in the brain and to the development of sickness and depression-like behaviour in this model.
A consideration of the possible recruitment of pro-inflammatory cytokines by non-infectious stimuli, such as hypoxia92
, through the release of catecholamines is also quite likely to provide new insights into the patho-physiology of the increased prevalence of depression in individuals with obstructive sleep apnea93
or chronic obstructive pulmonary disease94
Finally, the demonstration of a possible contribution of the immune system to the development of depression is likely to open new avenues in psychopathology. The cytokine theory of depression is certainly attractive for a field that is short of real innovations. However, the identification of the intracellular molecular mechanisms that are at the origin of the association between inflammation and depression will provide valuable targets for the development of new antidepressant drugs only if the activation of brain pro-inflammatory cytokine signalling is proven to represent the final common pathway for the various conditions that lead to depression. This task is still in its infancy.