Associate Editor: Peter HolzerImmune system to brain signaling: Neuropsychopharmacological implications☆
Introduction
Reciprocal interactions between the immune system and the brain have attracted considerable attention regarding the role of the immune system in neuropsychiatric diseases especially major depression. During the last several decades, research in the field referred to as “Psychoneuroimmunology” has demonstrated an intricate network of bi-directional relationships between the immune system and the brain. Alterations in immune function have been found in depressed patients with major depression and include early reports of immune suppression (e.g., reduced natural killer cell activity and reduced lymphocyte proliferation) followed by evidence of increased inflammatory activity (e.g., increased circulating levels of inflammatory markers) (Kronfol et al., 1983, Irwin and Gillin, 1987, Maes et al., 1993, Anisman et al., 1999, Zorrilla et al., 2001). Much of the recent interest in the role of the immune system in depression has focused on increased inflammation associated with depression. Pro-inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha, are released by activated immune cells during the host response to pathogen invasion as well as in the context of tissue injury and psychosocial stress. These soluble factors appear to represent primary mediators of the communication between the immune system and the brain, and not only help orchestrate cellular responses to immune challenge, but also coordinate the behavioral changes that are necessary for recovery. During the course of immune challenge, the release of pro-inflammatory cytokines is usually transient and regulated by anti-inflammatory mechanisms. Consequently, the behavioral effects triggered by the activation of the inflammatory response develop as an adaptative, temporary and controlled reaction of the central nervous system (CNS) to immune signals. Nevertheless, when immune challenge becomes chronic and/or unregulated, as is observed in patients receiving chronic cytokine treatments or those exposed to chronic medical illness and/or stress, the behavioral effects of cytokines and the resultant inflammatory response may contribute to the development of clinically relevant behavioral symptoms and neuropsychiatric diseases, including major depression. These immune-based behavioral disorders, as well as the pathophysiological mechanisms involved will be discussed in this review along with relevant treatment implications.
Section snippets
Sickness behavior
A rich database has been developed that substantiates the capacity of pro-inflammatory cytokines to induce, in addition to fever and activation of the hypothalamic–pituitary–adrenal (HPA) axis, a constellation of behavioral symptoms referred to as sickness behavior (Dantzer, 2001). Sickness behavior is typically associated with the behavioral changes seen in humans and laboratory animals suffering from microbial infections and includes depressive-like behavior, anhedonia, fatigue, psychomotor
How do cytokine signals access the brain?
Cytokines are relatively large molecules that do not freely pass through the blood brain barrier. Nevertheless, data indicate that cytokine signals are able to reach the brain through humoral, neural and cellular pathways (Fig. 2). These pathways are comprised of at least five non-exclusive mechanisms, including 1) passage of cytokines through leaky regions of the blood-brain barrier, including the choroid plexus and circumventricular organs, 2) active transport via saturable cytokine-specific
Pathophysiological mechanisms by which cytokines affect the brain
A number of pathways by which cytokines may influence behavior have been identified. These pathways include effects on neurotransmitter function, neuroendocrine activity, neural plasticity and alterations of brain circuitry (Fig. 3).
Sources of chronic inflammation
Chronic or non-resolving inflammation may originate from either pathophysiological (e.g., inflammatory diseases, immune-based disorders, T cell dysfunction) or non-pathological conditions including aging and obesity.
Translational implications
Given the vast knowledge base that has been elaborated regarding the capacity of inflammatory cytokines to influence behavior as well as the data detailing the potential mechanisms involved, there is a wide array of potential pharmacological and behavioral targets that may be relevant for the development of new treatments or prevention strategies for neuropsychiatric disorders including depression.
Conclusions
Brain–immune system interactions have opened up new vistas regarding the treatment and prevention of behavioral disorders. Given the interest in inflammation as a common mechanism of multiple diseases including cardiovascular disease, diabetes and cancer, the role of inflammation in neuropsychiatric diseases such as depression puts the neurosciences and psychiatry in lock step with other medical disciplines in identifying and targeting immune relevant molecules and pathways for the treatment of
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Conflict of interest: The authors declare no conflict of interest.